Phenyl derivative

ABSTRACT

wherein all the symbols have the same meanings as described in the specification, has two cyclic groups, particularly phenoxy groups at specific substitution positions and thus has high human S1P2 antagonistic activity. The compound may therefore be used as a therapeutic agent for S1P2-mediated diseases such as diseases resulting from vascular constriction, fibrosis, and respiratory diseases.

CROSS REFERENCE TO RELATED APPLICATION

This is a Division of U.S. patent application Ser. No. 15/784,376 filedOct. 16, 2017 (allowed), which is a Divisional of U.S. patentapplication Ser. No. 15/089,690 filed Apr. 4, 2016 (issued as U.S. Pat.No. 9,820,980 on Nov. 21, 2017) which is a Divisional of U.S. patentapplication Ser. No. 14/592,100 filed Jan. 8, 2015 (issued as U.S. Pat.No. 9,340,499 on May 17, 2016), which is a Continuation of U.S.application Ser. No. 14/347,178 filed Mar. 25, 2014 (issued as U.S. Pat.No. 8,975,409 on Mar. 10, 2015), which is a National Stage Entry of PCTInternational Application No. PCT/JP2012/074968 filed Sep. 27, 2012,which claims benefit of Japanese Patent Application No. 2011-213987filed Sep. 29, 2011 of which disclosures are incorporated herein byreference in their entirety.

TECHNICAL FIELD

The present invention relates to a compound represented by the formula(I-1):

wherein all the symbols have the same meanings as described hereinbelow,and a salt thereof, a solvate thereof, an N-oxide thereof or a prodrugthereof (hereinafter sometimes abbreviated as the present compound).

BACKGROUND ART

Sphingosine-1-phosphate[(2S,3R,4E)-2-amino-3-hydroxyoctadeca-4-enyl-1-phosphate; hereinaftersometimes abbreviated as S1P] is a lipid which is synthesized bymetabolic turnover of sphingolipids or extracellular action of secretorysphingosine kinases. It is proposed that this lipid acts as anintercellular transmitter and an intracellular secondary transmitter.

With regard to S1P₂ (EDG-5/AGR16/H218) receptors among S1P receptors, ithas been published that the strong expression of mRNA thereof isconfirmed in tissues of heart, lung, stomach and small intestine andthat the expression amount of mRNA thereof in intimal cells in modelmice of carotid balloon injury which are the model for coronaryarteriosclerosis is significantly decreased compared to normal intimalcells (see Patent Document 1).

It is also reported that S1P receptors (particularly S1P₂ receptors) areinvolved in portal hypertension, asthma and the like (see Non PatentDocument 1) It is also known that the receptors are involved inexpression of connective tissue growth factors (CTGFs) associated withonset of fibrosis, cancer and the like (see Non Patent Document 2).

The following compounds are known as the related art of the presentinvention.

As the compounds having S1P₂ antagonistic activity, pyrazopyridinecompounds or pharmaceutically acceptable salts thereof represented bythe formula (a):

wherein R^(1a), R^(2a) and R^(3a) represent a C1-8 alkyl group and thelike; R^(4a) represents a hydrogen atom and the like; R^(5a) and R^(6a)are the same or different and represent a hydrogen atom, a C1-8 alkylgroup, a C1-6 alkoxy group, a halogen atom and the like; X^(a)represents —NH—, —O—, —CH₂— and the like; Y^(a) represents —NH— and thelike; Z^(a) represents —CO— and the like; W^(a) represents —NH— and thelike; and the ring A^(a) represents an aryl group, a heteroaryl groupand the like (the definitions of respective groups are abstracted), havebeen disclosed which specifically act on S1P₂ receptors and are usefulas therapeutics for fibrosis (see Patent Document 2).

The known compounds having S1P₂ antagonistic activity also includecompounds having a piperidine skeleton represented by the formula (b):

[C 3]

A^(b)-X^(b)—Y^(b)—Z^(b)—B^(b)  (b)

wherein A^(b) represents a cyclic group which may contain a substituent;X^(b) represents a single bond or a spacer having 1 to 3 atoms in themain chain; Y^(b) represents a single bond or a spacer having 1 to 3atoms in the main chain; Z^(b) is a single bond or a spacer having 1 to3 atoms in the main chain; and B^(b) represents a cyclic group which maycontain a substituent (see Patent Document 3) and compounds having anazetidine skeleton (see Patent Document 4).

Meanwhile, as the compounds having a benzene skeleton substituted withtwo cyclic groups, the compounds represented by the formula (c):

wherein P₁ ^(c) and P₂ ^(c) independently represent a bond or a C₁₋₃alkyl; A^(c) represents CH or N; B^(c) represents CH or N; R₁ ^(c)represents a hydrogen, an amino, —NR₄ ^(c)—CO—Z^(c)R₉ ^(c)R₁₃ ^(c) andthe like; R₃ ^(c) represents —C(NR₁₇ ^(c))NH₂ or when A^(c) is CH, R₃^(c) also represents an amino C₁₋₇ alkyl; R₁₀ ^(c), R₁₄ ^(c) and R₁₅^(c) independently represent a hydrogen, a halogen, a C₁₋₇ alkyl and thelike; Q^(c) represents a hydrogen or a halogen; R₄ ^(c) represents ahydrogen or a C₁₋₇ alkyl; Z^(c) is a 5- to 12-membered saturated,partially saturated or aromatic ring which may be monocyclic orbicyclic; R₉ ^(c) and R₁₃ ^(c) independently represent a hydrogen, ahalogen, a C₁₋₇ alkyl and the like; R₂ ^(c) represents a C₁₋₇ alkyl, aphenyl which may be substituted and the like; and R₁₇ ^(c) represents ahydrogen, —OH, a C₁₋₇ alkoxy and the like (the definitions of respectivegroups are abstracted), are known as matriptase inhibitors (see PatentDocument 5).

No prior art documents discloses or suggests that the compound of theinvention which contains two cyclic groups, particularly phenoxy groupsat specific substitution positions have significantly improved humanS1P₂ antagonistic activity.

Patent Document 1: Japanese Patent Application Laid-open No. H6-234797

Patent Document 2: WO 01/98301

Patent Document 3: WO 2004/002531

Patent Document 4: WO 2005/063704

Patent Document 5: WO 2010/133748

Non Patent Document 1: Biochemical and Biophysical ResearchCommunications, vol. 320, No. 3, p. 754-759, 2004

Non Patent Document 2: Molecular Cancer Research, vol. 6, No. 10, p.1649-1656, 2008

DISCLOSURE OF THE INVENTION

A problem of the present invention is to find a compound having humanS1P₂ antagonistic activity which was insufficiently exhibited by thecompounds disclosed in Patent Document 3, to improve the solubility ofthe compound and to provide a medicinal product thereof.

The present inventors have carried out extensive studies in order tosolve the above problem to find the compound having improved human S1P₂antagonistic activity. As a result, the present inventors have foundthat the compound having two cyclic groups, particularly phenoxy groups,at certain substitution positions have significantly improved human S1P₂antagonistic activity compared to the compounds disclosed in PatentDocument 3, thereby completing the present invention.

Thus the present invention relates to:

[1] a compound represented by the formula (I-1):

wherein R¹ represents (1) a C1-8 alkyl group which may be substitutedwith 1 to 5 R²¹ group(s), (2) a C2-8 alkenyl group which may besubstituted with 1 to 5 R²¹ group(s), (3) a C2-8 alkynyl group which maybe substituted with 1 to 5 R²¹ group(s), (4) a C3-7 carbocycle which maybe substituted with 1 to 5 substituent(s) selected from the groupconsisting of a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxygroup and a halogen atom, or (5) —CONR³¹R³²;R²¹ represents (1) a halogen atom, (2) —OR²² (wherein, R²² represents(1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkylgroup), (3) —NR²³R²⁴ (wherein, R²³ and R²⁴ each independently represent(1) a hydrogen atom or (2) a C1-4 alkyl group) or (4) an oxo group;R³¹ and R³² each independently represent (1) a hydrogen atom or (2) aC1-4 alkyl group;R² represents (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4haloalkyl group;R³ and R⁴ each independently represent (1) a halogen atom, (2) a C1-4alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) ahydroxy group, (6) -L-CONR⁶R⁷, (7) -L-SO₂R⁸ or (8) -L-COOR⁹;R⁵ represents (1) a halogen atom, (2) a C1-4 alkyl group or (3) a C1-4haloalkyl group;L represents (1) a bond, (2) a group represented by the formula:

wherein A represents (1) a bond or (2) an oxygen atom; R¹² and R¹³ eachindependently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3)a hydroxy group or (4) NH₂ or (5) R¹² and R¹³ together with the carbonatom to which they are attached may form a C3-7 carbocycle; and thearrow on the right hand side binds to —CONR⁶R⁷, —SO₂R⁸ or —COOR⁹, (3) aC2-4 alkenylene group, (4) a —O—C2-4 alkenylene group, (5) an oxygenatom or (6) a nitrogen atom which may be substituted with a C1-4 alkylgroup;R⁶ and R⁷ each independently represent (1) a hydrogen atom, (2) a C1-4alkyl group, (3) a C1-4 haloalkyl group, (4) a hydroxy group, (5)—CONR¹⁵R¹⁶, (6) —SO₂NR¹⁵R¹⁶, (7) —COR¹⁷ or (8) —SO₂R¹⁷, or R⁶ and R⁷together with the nitrogen atom to which they are attached may form a 4-to 7-membered nitrogen-containing saturated heterocycle that may besubstituted with a hydroxy group;R⁸ represents (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group or (3)NR¹⁰R¹¹;R⁹ represents (1) a hydrogen atom or (2) a C1-8 alkyl group;R¹⁰ and R¹¹ each independently represent (1) a hydrogen atom, (2) a C1-4alkyl group, (3) —CONR¹⁵R¹⁶, (4) —SO₂NR¹⁵R¹⁶, (5) —COR¹⁷ or (6) —SO₂R¹⁷;the ring 1 and the ring 2 each independently represent a 5- to7-membered cyclic group;R¹⁴ represents (1) a hydrogen atom or (2) a hydroxy group;R¹⁵ and R¹⁶ each independently represent (1) a hydrogen atom, (2) a C1-4alkyl group or (3) a 5- to 7-membered cyclic group;R¹⁷ represents (1) a C1-4 alkyl group or (2) a 5- to 7-membered cyclicgroup;M¹ and M² each independently represent (1) a bond, (2) —C(O)—, (3) —O—,(4) —S—, (5) —C(O)O—, (6) —CH₂O— or (7) —C(O)NH—;n represents an integer of 1 to 2;m represents an integer of 1 to 2;p represents an integer of 0 to 5;q represents an integer of 0 to 5;r represents an integer of 0 to 4;t represents an integer of 1 to 4;when p is 2 or more, a plurality of R³ groups may be the same ordifferent;when q is 2 or more, a plurality of R⁴ groups may be the same ordifferent;when r is 2 or more, a plurality of R⁵ groups may be the same ordifferent; andwhen t is 2 or more, a plurality of R¹² and R¹³ groups may berespectively the same or different;a salt thereof, a solvate thereof, an N-oxide thereof or a prodrugthereof;[2] the compound according to [1], wherein R¹⁴ is a hydroxy group;[3] the compound according to [1] or [2], wherein M¹ and M² eachindependently are (1) —C(O)—, (2) —O—, (3) —S—, (4) —C(O)O— or (5)—CH₂O—;[4] the compound according to [3], wherein M¹ and M² are —O—;[5] the compound according to [1], which is represented by the formula(I):

wherein all the symbols have the same meanings as above;[6] the compound according to [5], wherein R¹ is (1) a C1-8 alkyl groupwhich may be substituted with 1 to 5 R²¹ group(s) or (2) a C3-7carbocycle which may be substituted with 1 to 5 substituent(s) selectedfrom the group consisting of a C1-4 alkyl group, a C1-4 alkoxy group, ahalogen atom and a trifluoromethyl group;[7] the compound according to [5] or [6], wherein R² is a hydrogen atom;[8] the compound according to any of [5] to [7], wherein the ring 1 andthe ring 2 each independently are (1) a benzene, (2) cyclohexane or (3)pyridine ring;[9] the compound according to any of [1] to [8], which is (1)4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidinecarboxamide,(2)4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicacid, (3)4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide,(4)2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid, (5)1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylic acid, (6)2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isobutyl-1-azetidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid, (7)4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoicacid, (8)2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicacid or (9)2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoicacid;[10] a pharmaceutical composition containing the compound represented bythe formula (I-1) according to [1], the salt thereof, the solvatethereof, the N-oxide thereof or the prodrug thereof;[11] the pharmaceutical composition according to [10], which is a S1P₂antagonist;[12] the pharmaceutical composition according to [10], which is aprophylactic and/or therapeutic agent for a S1P₂-mediated disease;[13] the pharmaceutical composition according to [12], wherein theS1P₂-mediated disease is a disease resulting from vascular constriction,fibrosis, respiratory disease, arteriosclerosis, peripheral arterialocclusive disease, retinopathy, glaucoma, age-related maculardegeneration, nephritis, diabetes, dyslipidemia, hepatitis, hepaticcirrhosis, hepatic failure, neuropathy, rheumatoid arthritis, wound,pain, urticaria, systemic lupus erythematosus (SLE) or cancer;[14] the pharmaceutical composition according to [13], wherein thedisease resulting from vascular constriction is cerebral vasospasticdisease, cardiac vasospastic disease, coronary vasospastic disease,hypertension, pulmonary hypertension, myocardial infarction, angina,arrhythmia, portal hypertension, varix or ischemia-reperfusion injury;[15] the pharmaceutical composition according to [13], wherein thefibrosis is pulmonary fibrosis, hepatic fibrosis, kidney fibrosis,myocardial fibrosis or skin fibrosis;[16] the pharmaceutical composition according to [13], wherein therespiratory disease is bronchial asthma, acute lung injury, sepsis orchronic obstructive pulmonary disease;[17] a method of preventing and/or treating a S1P₂-mediated disease,comprising administering to a mammal an effective amount of the compoundrepresented by the formula (I-1) according to [1], the salt thereof, thesolvate thereof, the N-oxide thereof or the prodrug thereof;[18] a compound represented by the formula (I-1) according to [1], thesalt thereof, the solvate thereof, the N-oxide thereof or the prodrugthereof in use for prophylaxis and/or therapy of a S1P₂-mediateddisease; and[19] use of the compound represented by the formula (I-1) according to[1], the salt thereof, the solvate thereof, the N-oxide thereof or theprodrug thereof for producing a prophylactic and/or therapeutic agentfor a S1P₂-mediated disease.

The present compound has strong human S1P₂ antagonistic activity, andthus is useful for therapy of S1P₂-mediated diseases such as diseasesresulting from vascular constriction and fibrosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction spectrum chart of a crystal of thepresent compound (Example A);

FIG. 2 is a differential scanning calorimetric (DSC) chart of a crystalof the present compound (Example A);

FIG. 3 is an X-ray powder diffraction spectrum chart of a crystal of thepresent compound (Example B);

FIG. 4 is a differential scanning calorimetric (DSC) chart of a crystalof the present compound (Example B);

FIG. 5 is an X-ray powder diffraction spectrum chart of a crystal of thepresent compound (Example C); and

FIG. 6 is a differential scanning calorimetric (DSC) chart of a crystalof the present compound (Example C).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail hereinbelow.

The halogen atom as used herein may include fluorine, chlorine, bromineor iodine.

The C1-8 alkyl group as used herein may include linear or branched C1-8alkyl groups which may include, for example, methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl,tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl,1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl,1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl,1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, 1-methylheptyl,2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl,1-propylpentyl, 2-propylpentyl, 1,5-dimethylhexyl,1-ethyl-4-methylpentyl, 1-propyl-3-methylbutyl, 1,1-dimethylhexyl,1-ethyl-1-methylpentyl or 1,1-diethylbutyl groups.

The C1-4 alkyl group as used herein may include linear or branched C1-4alkyl groups which may include, for example, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, sec-butyl or tert-butyl groups.

The C1-4 haloalkyl group as used herein may include a fluoromethylgroup, a chloromethyl group, a bromomethyl group, an iodomethyl group, adifluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a3-chloropropyl group, a 4,4,4-trifluorobutyl group or a 4-bromobutylgroup.

The C2-8 alkenyl group as used herein may include linear or branchedC2-8 alkenyl groups which may include, for example, vinyl, propenyl,butenyl, pentenyl, hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl,octadienyl, 2-methylpropen-1-yl, 2-ethyl-1-buten-1-yl,2-methylbuten-2-yl or 2-methylpenten-2-yl groups.

The C2-4 alkenylene group as used herein may include ethenylene,propenylene or butenylene groups.

The C2-8 alkynyl group as used herein may include linear or branchedC2-8 alkynyl groups which may include, for example, ethynyl, propynyl,butynyl, pentynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl, octynyl,octadiynyl or 3,3-dimethyl-1-butyn-1-yl groups.

The C1-4 alkoxy group as used herein may include, for example, methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy ortert-butoxy groups.

The C3-7 carbocycle as used herein means a C3-7 monocyclic carbocycle ora C3-7 carbocycle which may be partially or fully saturated and mayinclude, for example, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane, cyclobutene, cyclopentene, cyclohexene,cycloheptene, cyclobutadiene, cyclopentadiene, cyclohexadiene,cycloheptadiene or benzene rings.

The C5-7 carbocycle as used herein means a C5-7 monocyclic carbocycle ora C5-7 carbocycle which may be partially or fully saturated and mayinclude, for example, cyclopentane, cyclohexane, cycloheptane,cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene or benzene rings.

The 4- to 7-membered nitrogen-containing saturated heterocycle as usedherein refers to partially or fully saturated 4- to 7-memberedmonocyclic heterocycles which contain 1 to 5 hetero atoms selected froman oxygen atom, a nitrogen atom and a sulphur atom and inevitablycontain one or more nitrogen atoms. For example, azetidine, pyrroline,pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine,piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,dihydropyridazine, tetrahydropyridazine, perhydropyridazine,dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine,tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisooxazole(isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine or thiomorpholine rings may bementioned.

The 5- to 7-membered cyclic group as used herein means a C5-7 carbocycleand a 5- to 7-membered heterocycle. The C5-7 carbocycle has the samemeaning as above and the 5- to 7-membered heterocycle may include 5- to7-membered unsaturated heterocycles and 5- to 7-membered saturatedheterocycles. The 5- to 7-membered heterocycles may include, forexample, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran,tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin,tetrahydrooxepin, perhydrooxepin, dihydrothiopehene,tetrahydrothiopehene, dihydrothiopyran, tetrahydrothiopyran,dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole,tetrahydrooxazole (oxazolidine), dihydroisooxazole, tetrahydroisooxazole(isooxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine),dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine,tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine,dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine),dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine,tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine,perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine,perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, dioxolane,dioxane, dithiolane, dithiane, pyrrole, imidazole, triazole, tetrazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine,diazepine, furan, pyran, oxepin, thiopehene, thiopyran, thiepine,oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole,oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine,thiadiazine, thiazepine or thiadiazepine rings.

In the present invention, R¹ is preferably a C1-8 alkyl group which maybe substituted with 1 to 5 R²¹ group(s) or a C3-7 carbocycle which maybe substituted with 1 to 5 substituent(s) selected from the groupconsisting of a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxygroup and a halogen atom, and more preferably a branched C1-8 alkylgroup or a benzene, cyclopropane, cyclopentane, cyclohexane orcycloheptane ring which may be substituted with 1 to 5 substituent(s)selected from the group consisting of a halogen atom and atrifluoromethyl group. The branched C1-8 alkyl group is preferably anisopropyl, isobutyl, 2-ethylbutyl, 2-methylpentyl or 3-methylpentylgroup.

In the present invention, R² is preferably a hydrogen atom.

In the present invention, R³ is preferably a halogen atom or -L-COOR⁹.

In the present invention, R⁴ is preferably a halogen atom or -L-COOR⁹.

In the present invention, R⁵ is preferably a halogen atom or a C1-4alkyl group.

In the present invention, the ring 1 is preferably a benzene, pyridineor cyclohexane ring and more preferably a benzene ring.

In the present invention, the ring 2 is preferably a benzene, pyridineor cyclohexane ring and more preferably a benzene ring.

In the present invention, R¹⁴ is preferably a hydroxy group.

In the present invention, when M¹ represents —C(O)O—, —CH₂O— or—C(O)NH—, the orientation of binding of the respective groups is notparticularly limited; however it is preferable that the bond on theright hand side of the respective groups binds to the ring 1.

In the present invention, when M² represents —C(O)O—, —CH₂O— or—C(O)NH—, the orientation of binding of the respective groups is notparticularly limited; however it is preferable that the bond on theright hand side of the respective groups binds to the ring 2.

In the present invention, M¹ is preferably —C(O)—, —O—, —S—, —C(O)O— or—CH₂O— and more preferably —O—.

In the present invention, M² is preferably —C(O)—, —O—, —S—, —C(O)O— or—CH₂O— and more preferably —O—.

In the present invention, the compound represented by the formula (I-1)is preferably the compound represented by the formula (I).

In the present invention, the preferable compounds include the compoundsdescribed in Examples and more preferably (1)4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidinecarboxamide, (2)4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicacid, (3)4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide, (4)2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid, (5)1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylic acid, (6)2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isobutyl-1-azetidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid, (7)4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoicacid, (8)2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicacid, and (9)2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoicacid.

[Isomers]

The present invention encompasses all isomers unless particularlystated. For example, the alkyl group includes linear and branchedgroups. Moreover, the present invention encompasses geometrical isomersfor double bonds, rings and condensed rings (E-forms, Z-forms, cis formsand trans forms), optical isomers due to asymmetrical carbon atoms (Rand S forms, α and β configurations, enantiomers and diastereomers),optically active substances having optical rotating activity (D, L, dand 1 forms), polar substances which can be separated by chromatography(high polarity substances and low polarity substances), equilibriumcompounds, rotamers, mixtures thereof at arbitrary proportions andracemic mixtures. The present invention also encompasses tautomers.

The optical isomers according to the present invention may include notonly the ones with 100% purity but also the ones containing otheroptical isomers at less than 50%.

In the present invention, unless particularly stated, the symbol:

[C 8]

indicates that the bond projects below the plane of the paper (i.e. αconfiguration), the symbol:[C 9]

indicates that the bond projects above the plane of the paper (i.e. βconfiguration), and the symbol:[C 10]

indicates that the bond is the α configuration, the β configuration orthe mixture of these configurations at arbitrary proportions, asapparent to a person skilled in the art.

The compound represented by the formula (I-1) is converted to a salt bythe well-known method. The salt is preferably water-soluble. Appropriatesalts may include alkali metal (potassium, sodium and the like) salts,alkaline earth metal (calcium, magnesium and the like) salts, ammoniumsalts, pharmaceutically acceptable organic amine (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-glucamine and the like) salts, acid addition salts (inorganicacid salts (hydrochlorides, hydrobromides, hydroiodides, sulphates,phosphates, nitrates and the like), organic acid salts (acetates,trifluoroacetates, lactates, tartrates, oxalates, fumarates, maleates,benzoates, citrates, methanesulphonates, ethanesulphonates,benzenesulphonates, toluenesulphonates, isethionates, glucuronates,gluconates and the like) and the like) and the like.

The compound represented by the formula (I-1) and the salt thereof canalso be converted to a solvate. The solvate preferably has low toxicityand is water-soluble. Appropriate solvates may include, for example,solvates with water and alcoholic solvents (e.g. ethanol).

The N-oxide of the compound represented by the formula (I-1) refers tothe compound represented by the formula (I-1) in which the nitrogen atomis oxidized. The N-oxide of the compound represented by the formula(I-1) may also be the alkali (alkaline earth) metal salt, the ammoniumsalt, the organic amine salt and the acid addition salt as describedabove.

The prodrug of the compound represented by the formula (I-1) refers to acompound which is converted in vivo to the compound represented by theformula (I-1) by the reaction with enzymes, gastric acid and the like.The prodrug of the compound represented by the formula (I-1) mayinclude, when the compound represented by the formula (I-1) has ahydroxy group, compounds in which the hydroxy group is acylated,alkylated, phosphorylated or converted to borate (e.g. the presentcompounds in which the hydroxy group is converted to acetyl, palmitoyl,propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl or the like); compounds represented by theformula (I-1) in which the carboxyl group is esterified or amidated(e.g. compounds represented by the formula (I-1) in which the carboxylgroup is converted to ethyl ester, isopropyl ester, phenyl ester,carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methylamide or the like) and the like.These compounds can be produced by the well-known methods. The prodrugof the compound represented by the formula (I-1) may be hydrates ornon-hydrates. The prodrug of the compound represented by the formula(I-1) may be the one which is converted to the compound represented bythe formula (I-1) under the physiological condition such as thosedisclosed in “Iyakuhin no Kaihatsu”, vol. 7 “Bunshi Sekkei”, p. 163-198,1990, Hirokawa Shoten Co. The compound represented by the formula (I-1)may be labelled with an isotope (for example, ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I and the like).

[Production Method of the Present Compound]

The present compound can be produced by well-known methods, for example,the method described in Comprehensive Organic Transformations: A Guideto Functional Group Preparations, 2nd Edition (Richard C. Larock, JohnWiley & Sons Inc, 1999) or the method described in Examples withappropriate modifications and combinations.

The compound having the formula (I) in which R² is a hydrogen atom,namely the compound represented by the formula (I-A):

wherein all the symbols have the same meanings as above, can be producedas shown in the following reaction step formula 1:

[C 12] Reaction Step Formula 1

wherein T represents a protecting group of the amino group having thecarbonyl group (e.g. a 2,2,2-trichloroethoxycarbonyl(Troc) group, aphenoxycarbonyl group, a p-nitrophenoxycarbonyl group and the like); X¹,X² and X³ each independently represent a halogen atom and X¹, X² and X³may be the same or different; and other symbols have the same meaningsas above.

In the reaction step formula 1, the reaction 1 can be carried out as anetherification reaction between the compound represented by the formula(A) and the compound represented by the formula (II). Thisetherification reaction is well known and is carried out, for example,in an organic solvent (N,N-dimethylacetamide, N,N-dimethylformamide,dimethyl sulphoxide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, methyl t-butyl ether and the like), in the presence ofan alkali metal hydroxide (sodium hydroxide, potassium hydroxide,lithium hydroxide and the like), an alkali metal hydride (sodium hydrideand the like), an alkaline earth metal hydroxide (barium hydroxide,calcium hydroxide and the like), a phosphate (potassium phosphate andthe like) or a carbonate (caesium carbonate, sodium carbonate, potassiumcarbonate and the like) or an aqueous solution thereof or a mixturethereof and at 0 to 100° C.

In the reaction step formula 1, the reaction 2 can be carried out as anetherification reaction, as the reaction 1, using the compoundrepresented by the formula (B) and the compound represented by theformula (III).

In the reaction step formula 1, the reaction 3 can be carried out as areduction reaction of the nitro group of the compound represented by theformula (C). The reduction reaction of the nitro group is well known andis carried out, for example, by the methods described hereinbelow.

(1) The reaction is carried out, for example, in a solvent [ethers(tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether and the like),alcohols (methanol, ethanol and the like), benzenes (benzene, tolueneand the like), ketones (acetone, methyl ethyl ketone and the like),nitriles (acetonitrile and the like), amides (dimethylformamide and thelike), water, ethyl acetate, acetic acid or mixed solvents of two ormore of the above], in the presence of a hydrogenation catalyst(palladium-carbon, palladium black, palladium, palladium hydroxide,platinum dioxide, platinum-carbon, nickel, Raney nickel, rutheniumchloride and the like), in the presence or absence of an acid(hydrochloric acid, sulphuric acid, hypochlorous acid, boric acid,tetrafluoroboric acid, acetic acid, p-toluenesulphonic acid, oxalicacid, trifluoroacetic acid, formic acid and the like), in an hydrogenatmosphere of normal or increased pressure, in the presence of ammoniumformate or hydrazine and at a temperature of 0 to 200° C.

(2) The reaction is carried out, for example, in a water-misciblesolvent (ethanol, methanol, tetrahydrofuran and the like), in thepresence or absence of an acid (hydrochloric acid, hydrobromic acid,ammonium chloride, acetic acid, ammonium formate and the like), by usinga metal reagent (zinc, iron, tin, tin chloride, iron chloride, samarium,indium, sodium borohydride-nickel chloride and the like) at atemperature of 0 to 150° C.

In the reaction step formula 1, the reaction 4 is well known and iscarried out with the compound represented by the formula (D) and thecompound represented by the formula (IV), for example, by reaction ofthe compound represented by the formula (IV) in the presence of a base(pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine and the like) with the compound represented by theformula (D) in an organic solvent (chloroform, dichloromethane, diethylether, tetrahydrofuran and the like) at a temperature of 0 to 40° C. Thecompound represented by the formula (IV) can also be subjected to thereaction with the formula (D) in an organic solvent (ethyl acetate,dioxane, tetrahydrofuran and the like), with using an alkaline aqueoussolution (sodium hydrogen carbonate solution, sodium hydroxide solutionand the like) at 0 to 40° C.

In the reaction step formula 1, the reaction 5 is well known and iscarried out with the compound represented by the formula (E) and thecompound represented by the formula (V), for example, by reaction of thecompound represented by the formula (E) in the presence of a base(pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine and the like) with the compound represented by theformula (V) in an organic solvent (N,N-dimethylacetamide, chloroform,dichloromethane, diethyl ether, tetrahydrofuran and the like) at atemperature of 0° C. to a reflux temperature.

In the reaction step formula 1, when the compound represented by theformula has a protecting group, for example, when R³ or R⁴ is protected,deprotection reaction may be carried out if necessary. Deprotectionreaction of protecting groups is well known and can be carried out byfollowing methods which may include, for example, (1) deprotectionreaction by alkaline hydrolysis, (2) deprotection reaction under acidicconditions, (3) deprotection reaction by hydrolysis, (4) deprotectionreaction of silyl groups, (5) deprotection reaction using a metal, (6)deprotection reaction using a metal complex and the like.

These methods are specifically described hereinbelow.

(1) Deprotection reaction by alkaline hydrolysis is carried out, forexample, in an organic solvent (e.g. methanol, tetrahydrofuran anddioxane), by using an alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide and lithium hydroxide), an alkaline earth metalhydroxide (e.g. barium hydroxide and calcium hydroxide) or a carbonate(e.g. sodium carbonate and potassium carbonate) or an aqueous solutionthereof or a mixture thereof at 0 to 40° C.

(2) Deprotection reaction under acidic conditions is carried out, forexample, in an organic solvent (e.g. dichloromethane, chloroform,dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran andanisole) and in an organic acid (e.g. acetic acid, trifluoroacetic acid,methanesulphonic acid and p-tosylic acid) or an inorganic acid (e.g.hydrochloric acid and sulphuric acid) or a mixture thereof (e.g.hydrogen bromide/acetic acid) in the presence or absence of2,2,2-trifluoroethanol at 0 to 100° C.

(3) Deprotection reaction by hydrolysis is carried out, for example, ina solvent (e.g. ethers (e.g. tetrahydrofuran, dioxane, dimethoxyethaneand diethyl ether), alcohols (e.g. methanol and ethanol), benzenes (e.g.benzene and toluene), ketones (e.g. acetone and methyl ethyl ketone),nitriles (e.g. acetonitrile), amides (e.g. N,N-dimethylformamide),water, ethyl acetate, acetic acid or mixed solvents of two or more ofthe above), in the presence of a catalyst (e.g. palladium-carbon,palladium black, palladium hydroxide-carbon, platinum oxide and Raneynickel), in a hydrogen atmosphere of normal or increased pressure or inthe presence of ammonium formate at 0 to 200° C.

(4) Deprotection reaction of silyl groups is carried out, for example,in a water-miscible organic solvent (e.g. tetrahydrofuran andacetonitrile), by using tetrabutylammonium fluoride at 0 to 40° C.Alternatively, the reaction is carried out, for example, in an organicacid (e.g. acetic acid, trifluoroacetic acid, methanesulphonic acid andp-tosylic acid) or an inorganic acid (e.g. hydrochloric acid andsulphuric acid) or a mixture thereof (e.g. hydrogen bromide/acetic acid)at −10 to 100° C.

(5) Deprotection reaction using a metal is carried out, for example, inan acidic solvent (e.g. acetic acid, a buffer of pH 4.2 to 7.2 or amixed solution thereof with an organic solvent such as tetrahydrofuran)in the presence of zinc powder with application of ultrasonic, ifnecessary, at 0 to 40° C.

(6) Deprotection reaction using a metal complex is carried out, forexample, in an organic solvent (e.g. dichloromethane,N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,dioxane and ethanol), water or a mixed solvent thereof in the presenceof a trap reagent (e.g. tributyltin hydride, triethylsilane, dimedone,morpholine, diethylamine and pyrrolidine), in the presence of an organicacid (e.g. acetic acid, formic acid and 2-ethylhexanoic acid) and/or asalt of an organic acid (e.g. sodium 2-ethylhexanoate and potassium2-ethylhexanoate), in the presence or absence of a phosphine reagent(e.g. triphenylphosphine), with using a metal complex (e.g. tetrakistriphenylphosphine palladium (0), bis(triphenylphosphine)palladium (II)dichloride, palladium (II) acetate and tris(triphenylphosphine)rhodium(I) chloride) at 0 to 40° C.

Alternatively, the deprotection reaction can be carried out by themethod described in, for example, T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York, 1999.

The protecting group of a hydroxy group may include, for example, amethyl group, a trityl group, a methoxymethyl (MOM) group, a1-ethoxyethyl (EE) group, a methoxyethoxymethyl (MEM) group, a2-tetrahydropyranyl (THP) group, a trimethylsilyl (TMS) group, atriethylsilyl (TES) group, a t-butyldimethylsilyl (TBDMS) group, at-butyldiphenylsilyl (TBDPS) group, an acetyl (Ac) group, a pivaloylgroup, a benzoyl group, a benzyl (Bn) group, a p-methoxybenzyl group, anallyloxycarbonyl (Alloc) group, a 2,2,2-trichloroethoxycarbonyl (Troc)group and the like.

The protecting group of an amino group may include, for example, abenzyloxycarbonyl group, a t-butoxycarbonyl group, an allyloxycarbonyl(Alloc) group, a 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, atrifluoroacetyl group, a 9-fluorenylmethoxycarbonyl group, a benzyl (Bn)group, a p-methoxybenzyl group, a benzyloxymethyl (BOM) group, a2-(trimethylsilyl)ethoxymethyl (SEM) group and the like.

The protecting group of a hydroxy group and an amino group is notparticularly limited to those mentioned above as far as it can bereadily and selectively eliminated. For example, the ones described inT. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York,1999 may be used.

In the reactions described herein, the compounds used as startingmaterials such as the formulae (A), (II), (III), (IV) and (V) are wellknown or can be readily produced according to well-known methods.

In the reactions described herein, reactions accompanied by heating canbe carried out, as apparent to a person skilled in the art, with a waterbath, an oil bath, a sand bath or a microwave.

In the reactions described herein, a solid phase immobilized reagentwhich is immobilized on a high molecular polymer (e.g. polystyrene,polyacrylamide, polypropylene and polyethylene glycol) may be used.

In the reactions described herein, reaction products can be purifiedaccording to a conventional purification means such as distillation atnormal or reduced pressure, high performance liquid chromatography usingsilica gel or magnesium silicate, thin layer chromatography, ionexchange resins, scavenger resins or column chromatography or washingand re-crystallization. Purification can be carried out after eachreaction or after a few reactions.

[Toxicity]

The present compound has sufficiently low toxicity and thus can be usedsafely as a medicament.

[Application to Medicaments]

The present compound has S1P₂ antagonistic activity and thus is usefulas a prophylactic and/or therapeutic agent for a S1P₂-mediated disease.The S1P₂-mediated disease may include a disease resulting from vascularconstriction, fibrosis, a respiratory disease, arteriosclerosis,peripheral arterial occlusive disease, retinopathy, glaucoma,age-related macular degeneration, nephritis, diabetes, dyslipidemia,hepatitis, hepatic cirrhosis, hepatic failure, neuropathy, rheumatoidarthritis, wound, pain, urticaria, systemic lupus erythematosus (SLE),cancer and the like.

The disease resulting from vascular constriction as used herein mayinclude cerebral vasospastic disease, cardiac vasospastic disease,coronary vasospastic disease, hypertension, pulmonary hypertension,myocardial infarction, angina, arrhythmia, portal hypertension, varix,ischemia-reperfusion injury and the like.

The fibrosis as used herein may include pulmonary fibrosis, hepaticfibrosis, kidney fibrosis, myocardial fibrosis, skin fibrosis and thelike.

The respiratory disease as used herein may include bronchial asthma,acute lung injury, sepsis, chronic obstructive pulmonary disease and thelike.

The present compound may be combined with another drug so as to beadministered as a concomitant drug in order to:

1) complement and/or enhance the prophylactic and/or therapeutic effectof the present compound;2) improve kinetics and uptake and reduce the dosage of the presentcompound; and/or3) decrease side effect of the present compound.

The concomitant drug of the present compound and another drug may beadministered as a combined agent containing both components in oneformulation or administered separately. This separate administrationincludes simultaneous administration and sequential administration. Thesequential administration may include the administration of the presentcompound prior to another drug and the administration of another drugprior to the present compound. The manners of administration of thecomponents may be the same or different.

The concomitant drug may exhibit prophylactic and/or therapeutic effectfor any diseases without limitation as far as the prophylactic and/ortherapeutic effect of the present compound is complemented and/orenhanced.

Another drug which is used for complementation and/or enhancement of theprophylactic and/or therapeutic effect of the present compound for thedisease resulting from vascular constriction may include, for example,calcium antagonists, thrombolytic agents, thromboxane synthaseinhibitors, endothelin antagonists, antioxidants, radical scavengers,PARP inhibitors, astrocyte function improving agents, Rho kinaseinhibitors, angiotensin II antagonists, angiotensin-converting enzymeinhibitors, diuretic agents, phosphodiesterase (PDE) 4 inhibitors,prostaglandins (hereinafter sometimes abbreviated as PG or PGs),aldosterone antagonists, endothelin antagonists, prostacyclinformulations, nitrates, β-blockers, vasodilators and the like.

Another drug which is used for complementation and/or enhancement of theprophylactic and/or therapeutic effect of the present compound forfibrosis may include, for example, steroids, immunosuppressants, TGF-βinhibitors, PDE5 inhibitors and the like.

Another drug which is used for complementation and/or enhancement of theprophylactic and/or therapeutic effect of the present compound for therespiratory disease may include, for example, PDE4 inhibitors, steroids,β-agonists, leukotriene receptor antagonists, thromboxane synthaseinhibitors, thromboxane A2 receptor antagonists, mediator releasesuppressing agents, antihistamines, xanthine derivatives,anticholinergic agents, cytokine inhibitors, PGs, forskolinformulations, elastase inhibitors, metalloprotease inhibitors,expectorants, antibiotics and the like.

The calcium antagonists may include, for example, nifedipine, benidipinehydrochloride, diltiazem hydrochloride, verapamil hydrochloride,nisoldipine, nitrendipine, bepridil hydrochloride, amlodipine besylate,lomerizine hydrochloride, efonidipine hydrochloride and the like.

The thrombolytic agents may include, for example, alteplase, urokinase,tisokinase, nasaruplase, nateplase, tissue plasminogen activator,pamiteplase, monteplase and the like.

The thromboxane synthase inhibitors may include, for example, ozagrelhydrochloride, imitrodast sodium and the like. The radical scavengersmay include, for example, Radicut and the like.

The PARP inhibitors may include, for example, 3-aminobenzamide,1,3,7-trimethylxanthine, PD-141076, PD-141703 and the like.

The astrocyte function improving agents may include, for example,ONO-2506 and the like.

The Rho kinase inhibitors may include, for example, fasudilhydrochloride and the like.

The angiotensin II antagonists may include, for example, losartan,candesartan, valsartan, irbesartan, olmesartan, telmisartan and thelike.

The angiotensin-converting enzyme inhibitors may include, for example,alacepril, imidapril hydrochloride, quinapril hydrochloride, temocaprilhydrochloride, delapril hydrochloride, benazepril hydrochloride,captopril, trandolapril, perindopril erbumine, enalapril maleate,lisinopril and the like.

The diuretic agents may include, for example, mannitol, furosemide,acetazolamide, dichlorphenamide, methazolamide, trichlormethiazide,mefruside, spironolactone, aminophyline and the like.

The PDE4 inhibitors may include, for example, rolipram, cilomilast,Bay19-8004, NIK-616, roflumilast, cipamfylline, atizoram, SCH-351591,YM-976, V-11294A, PD-168787, ONO-6126, D-4396, IC-485 and the like.

The prostaglandins (PGs) may include, for example, PG receptor agonists,PG receptor antagonists and the like.

The PG receptor may include, for example, PGE receptors (EP1, EP2, EP3and EP4), PGD receptors (DP and CRTH2), a PGF receptor (FP), a PGIreceptor (IP), a thromboxane receptor (TP) and the like.

The aldosterone antagonists may include, for example, drospirenone,metyrapone, canrenoate potassium, canrenone, eplerenone, ZK-91587 andthe like.

The prostacyclin formulations may include, for example, treprostinilsodium, epoprostenol sodium, beraprost sodium and the like.

The nitrates may include, for example, amyl nitrite, nitroglycerin,isosorbide dinitrate and the like.

The β-blockers may include, for example, alprenolol hydrochloride,bupranolol hydrochloride, bufetolol hydrochloride, oxprenololhydrochloride, atenolol, bisoprolol fumarate, betaxolol hydrochloride,bevantolol hydrochloride, metoprolol tartrate, acebutolol hydrochloride,celiprolol hydrochloride, nipradilol, tilisolol hydrochloride, nadorol,propranolol hydrochloride, indenolol hydrochloride, carteololhydrochloride, pindolol, bunitrolol hydrochloride, landiololhydrochloride, esmolol hydrochloride, arotinolol hydrochloride,carvedilol, timolol maleate and the like.

The vasodilators may include, for example, diltiazem hydrochloride,trimetazidine hydrochloride, dipyridamole, etanofen hydrochloride,dilazep hydrochloride, trapidil, nicorandil and the like.

The steroids may include, as agents for oral administration orinjection, for example cortisone acetate, hydrocortisone, hydrocortisonesodium phosphate, hydrocortisone sodium succinate, fludrocortisoneacetate, prednisolone, prednisolone acetate, prednisolone sodiumsuccinate, prednisolone butylacetate, prednisolone sodium phosphate,halopredone acetate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, triamcinolone, triamcinolonediacetate, triamcinolone acetonide, dexamethasone, dexamethasoneacetate, dexamethasone sodium phosphate, dexamethasone palmitate,paramethasone acetate, betamethasone and the like. The steroids forinhalation may include, for example, beclomethasone propionate,fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P,ciclesonide, dexamethasone palomithionate, mometasone furonate,prasterone sulphonate, deflazacort, methylprednisolone sleptanate,methylprednisolone sodium succinate and the like.

The immunosuppressants may include, for example, azathioprine,mizoribine, methotrexate, mycophenolate mofetil, cyclophosphamide,cyclosporine A, tacrolimus, sirolimus, everolimus, prednisolone,methylprednisolone, orthoclone OKT3, anti-human lymphocyte globulin,deoxyspergualin and the like.

The PDE5 inhibitors may include, for example, sildenafil, tadalafil,vardenafil, udenafil and the like.

The β agonists may include, for example, fenoterol hydrobromide,salbutamol sulphate, terbutaline sulphate, formoterol fumarate,salmeterol xinafoate, isoproterenol sulphate, orciprenaline sulphate,clorprenaline sulphate, epinephrine, trimetoquinol hydrochloride,hexoprenaline mesyl sulphate, procaterol hydrochloride, tulobuterolhydrochloride, tulobuterol, pirbuterol hydrochloride, clenbuterolhydrochloride, mabuterol hydrochloride, ritodrine hydrochloride,bambuterol, dopexamine hydrochloride, meluadrine tartrate, AR-C68397,levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211, AR-C89855, S-1319and the like.

The leukotriene receptor antagonists may include, for example,pranlukast hydrate, montelukast, zafirlukast, seratrodast and the like.

The thromboxane A2 receptor antagonists may include, for example,seratrodast, ramatroban, domitroban calcium hydrate and the like.

The mediator release suppressing agents may include, for example,tranilast, cromolyn sodium, amlexanox, repirinast, ibudilast,tazanolast, pemirolast potassium and the like.

The antihistamines may include, for example, ketotifen fumarate,mequitazine, azelastine hydrochloride, oxatomide, terfenadine,emedastine fumarate, epinastine hydrochloride, astemizole, ebastine,cetirizine hydrochloride, bepotastine, fexofenadine, loratadine,desloratadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530,mometasone furoate, mizolastine, BP-294, andolast, auranofin,acrivastine and the like.

The xanthine derivatives may include, for example, aminophylline,theophylline, doxofylline, cipamfylline, diprophylline and the like.

The anticholinergic agents may include, for example, ipratropiumbromide, oxytropium bromide, flutropium bromide, cimetropium bromide,temiverine, tiotropium bromide, revatropate and the like.

The cytokine inhibitors may include, for example, suplatast tosilate andthe like.

The elastase inhibitors may include, for example, ONO-5046, ONO-6818,MR-889, PBI-1101, EPI-HNE-4, R-665 and the like.

The expectorants may include, for example, foeniculated ammonia spirit,sodium hydrogen carbonate, bromhexine hydrochloride, carbocysteine,ambroxol hydrochloride, ambroxol hydrochloride sustained releasepreparation, methylcysteine hydrochloride, acetylcysteine,L-ethylcysteine hydrochloride, tyloxapol and the like.

The antibiotics may include, for example, cefuroxime sodium, meropenemtrihydrate, netilmicin sulphate, sisomicin sulphate, ceftibuten,PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromicin sulphate,cefetamet pivoxil hydrochloride and the like. The antibiotics forinhalation may include, for example, PA-1806, IB-367, tobramycin,PA-1420, doxorubicin, astromicin sulphate, cefetamet pivoxilhydrochloride and the like.

The drug which is combined with the present compound encompasses notonly the known compounds but also the compounds which will be found infuture.

The present compound is usually administered systemically or locally inan oral or parenteral form. Oral formulations may include, for example,liquids for oral administration (e.g. elixirs, syrups, pharmaceuticallyacceptable solutions, suspensions and emulsions), solid agents for oraladministration (e.g. tablets (including sublingual tablets and oraldisintegration tablets), pills, capsules (including hard capsules, softcapsules, gelatine capsules and microcapsules), powders, granules andtroches) and the like. Parenteral formulations may include, for example,liquids (e.g. injections (subcutaneous injections, intravenousinjections, intramuscular injections, intraperitoneal injections,infusions and the like), ophthalmic solutions (e.g. aqueous ophthalmicsolutions (aqueous ophthalmic solutions, aqueous ophthalmic suspensions,viscous ophthalmic solutions and solubilized ophthalmic solutions),non-aqueous ophthalmic solutions (non-aqueous ophthalmic solutions,non-aqueous ophthalmic suspensions and the like)) and the like), topicalformulations (e.g. ointments (ophthalmic ointments and the like)),eardrops and the like. These formulations may be controlled-releasepreparations such as prompt release preparations or sustained releasepreparations. These formulations can be produced according to well-knownmethods such as the method described in Japanese Pharmacopoeia and thelike.

The liquids for oral administration are produced by, for example,dissolving, suspending or emulsifying the active ingredient in a diluentthat is generally used (e.g. purified water, ethanol and a mixturethereof). The liquids may further contain a wetting agent, a suspendingagent, an emulsifying agent, a sweetening agent, a flavouring agent, anaroma, a preservative, a buffering agent and the like.

The solids for oral administration are formulated according toconventional methods by, for example, mixing the active ingredient witha vehicle (e.g. lactose, mannitol, glucose, microcrystalline celluloseand starch), a binder (e.g. hydroxypropyl cellulose,polyvinylpyrrolidone and magnesium aluminometasilicate), a disintegrant(e.g. calcium carboxymethyl cellulose), a lubricant (e.g. magnesiumstearate), a stabiliser, a solution adjuvant (glutamic acid, asparticacid and the like) and the like. The solids may be, if desired, coatedwith a coating agent (e.g. sucrose, gelatine, hydroxypropyl celluloseand hydroxypropyl methylcellulose phthalate) and may be coated with twoor more layers.

The topical formulations as parenteral formulations are producedaccording to well-known methods or conventional formulations. Forexample, ointments are produced by triturating or melting the activeingredient in a base. The base for ointments is selected among thosewell-known or conventionally used. One or more selected from thefollowings, for example, may be used solely or in combination: a higherfatty acid or higher fatty acid ester (e.g. adipic acid, myristic acid,palmitic acid, stearic acid, oleic acid, adipate ester, myristate ester,palmitate ester, stearate ester and oleate ester), a wax (e.g. beeswax,whale wax and ceresin), a surfactant (e.g. polyoxyethylene alkyl etherphosphate esters), a higher alcohol (e.g. cetanol, stearyl alcohol andcetostearyl alcohol), a silicone oil (e.g. dimethylpolysiloxane), ahydrocarbon (e.g. hydrophilic petrolatum, white petrolatum, purifiedlanolin and liquid paraffin), a glycol (e.g. ethylene glycol, diethyleneglycol, propylene glycol, polyethylene glycol and macrogol), vegetableoil (e.g. castor oil, olive oil, sesame oil and turpentine oil), animaloil (e.g. mink oil, egg-yolk oil, squalane and squalene), water, anabsorption enhancing agent and a rash preventing agent. The formulationsmay further contain a humectant, a preservative, a stabilizer, anantioxidant, an aroma conferring agent and the like.

The injections as parenteral formulations encompass solutions,suspensions, emulsions and solid injections which are dissolved orsuspended in a solvent upon use. The injections are used by, forexample, dissolving, suspending or emulsifying the active ingredient ina solvent. The solvent used is, for example, distilled water forinjections, saline, vegetable oil, propylene glycol, polyethyleneglycol, alcohols such as ethanol or a combination thereof. Theinjections may further contain a stabilizer, a solution adjuvant (e.g.glutamic acid, aspartic acid and Polysolvate 80®), a suspending agent,an emulsifying agent, a soothing agent, a buffering agent, apreservative and the like. The injections are produced by sterilizationat the final stage or through an aseptic manipulation. Alternatively,aseptic solid formulations, for example freeze-dried formulations, maybe produced which may be dissolved, before use, in sterilized or asepticdistilled water for injection or another solvent.

For the purposes described above, the present compound or a concomitantagent of the present compound and another drug is generally administeredsystemically or locally in an oral or parenteral form. The dosage mayvary according to the age, weight, symptoms, therapeutic effect, themanner of administration, treatment period and the like, and may begenerally administered orally at a single dose for an adult of from 1 ngto 1000 mg with one or a few times daily, or administered parenterallyat a single dose for an adult of from 0.1 ng to 10 mg with one or a fewtimes daily, or continuously administered intravenously for 1 hour to 24hours daily. The dosage may vary, as described above, according tovarious conditions, of course, and thus the dosage which is less thanthe range described above may be sufficient in some cases and the dosagewhich is more than the range described above may be required in somecases.

EXAMPLES

The present invention is hereinbelow described in detail by way ofExamples which do not limit the present invention.

The solvents described in brackets in the sections of chromatographyseparation and TLC indicate the elution solvents or developing solventsused and the proportions are represented by volume ratios.

The solvents described in brackets in the sections of NMR indicate thesolvents used for the measurements.

The compounds are denominated in the present specification by using acomputer programme, ACD/Name® from Advanced Chemistry Development whichgenerally denominates according to the rules from IUPAC, or according tothe IUPAC nomenclature system.

Example 1: Methyl[4-(benzyloxy)phenyl]acetate

At room temperature, to a 3-L pear-shaped evaporating flask was addedmethyl(4-hydroxyphenyl)acetate (202 g) and potassium carbonate (233 g)which were dissolved in N,N-dimethylacetamide (DMA) (1 L). To thesolution was added benzyl chloride (117 mL) at room temperature andstirred. The solution was then heated to 60° C. and stirred for 16hours. The reaction solution was cooled to room temperature, dilutedwith methyl tert-butylether (MTBE) (1.3 L) and added with water (3 L)and an organic layer was extracted. The resulting organic layer waswashed three times with a 1 N sodium hydroxide aqueous solution, thenwith water and a saturated sodium chloride solution and then dried overanhydrous magnesium sulphate. The solvent was distilled off at reducedpressure to give the titled compound (245 g) having the followingphysical properties.

TLC: Rf 0.68 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 3.56 (3H), 3.68 (3H), 5.05 (2H), 6.93 (3H), 7.19 (2H),7.26-7.50 (5H).

Example 2: Methyl 2-[4-(benzyloxy)phenyl]-2-methylpropanoate

Under an argon atmosphere, to a 1-L four-neck flask was added thecompound prepared in Example 1 (66.5 g) which was dissolved intetrahydrofuran (THF) (260 mL). The solution was cooled to −10° C. andsequentially added with methyl iodide (8.1 mL) and a 1.53 M solution ofpotassium tert-butoxide (85 mL) in THF while the internal temperature ofthe reaction solution was maintained at −10° C. to −7.5° C. Thisprocedure was repeated eight times. The solution was then stirred at−10° C. for 10 minutes and slowly added dropwise with acetic acid (50.5mL). The solution was neutralized with a 2 N sodium hydroxide aqueoussolution and saturated aqueous sodium bicarbonate and extracted withethyl acetate and hexane. The extract was washed with water and asaturated sodium chloride solution and then dried over anhydrousmagnesium sulphate. The solvent was then distilled off under reducedpressure. Activated carbon (4 g) was then added thereto, the mixture wasstirred at room temperature for 30 minutes, the activated carbon wasfiltered off, and the solvent was distilled off under reduced pressureto give the titled compound (73.0 g) having the following physicalproperties.

TLC: Rf 0.54 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.55 (6H), 3.64 (3H), 5.05 (2H), 6.93 (2H), 7.26 (2H),7.30-7.48 (5H).

Example 3: Methyl 2-(4-hydroxyphenyl)-2-methylpropanoate

Under an argon atmosphere, to a 2-L pear-shaped evaporating flask wasadded a solution of the compound prepared in Example 2 (72.0 g) inmethanol (420 mL) mixed with ethyl acetate (150 mL). After purged withargon, 20% palladium carbon (7.60 g) was added. The flask was degassedand charged with hydrogen gas. The flask was vigorously stirred at roomtemperature for 4 hours. The reaction system was purged with argon,filtered with celite and washed with ethyl acetate. The filtrate wassubjected to distillation under reduced pressure followed by dilutionwith ethyl acetate (150 mL) and hexane (50 mL). The diluted solution wasdried over anhydrous magnesium sulphate and the solvent was distilledoff to obtain a gray-white solid (50 g). The solid was dissolved inethyl acetate (70 mL) while heating which was then added with hexane(700 mL) and stirred at room temperature. The precipitated solid wascollected by filtration, washed with hexane/ethyl acetate (10:1) anddried to give the titled compound (41.1 g) having the following physicalproperties.

TLC: Rf 0.27 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.55 (6H), 3.65 (3H), 6.77 (2H), 7.19 (2H)

Example 4: Methyl2-[4-(3-fluoro-5-nitrophenoxy)phenyl]-2-methylpropanoate

Under an argon atmosphere and at room temperature, to a 500-mLpear-shaped evaporating flask were added the compound prepared inExample 3 (41.1 g) and potassium phosphate (81.5 g). To the reactionsystem was added 1,3-difluoro-5-nitrobenzene (30.6 g) dissolved in DMA(128 mL) and stirred. The reaction system was then heated to 70° C. andstirred for 6.5 hours. The reaction solution was cooled to roomtemperature, diluted with MTBE (150 mL) and added with ice water (150mL) before stirring. An organic layer was extracted by adding MTBE andwater. The aqueous layer was added with MTBE and water to extract anorganic layer. The organic layer was combined, washed twice with a 1 Nsodium hydroxide aqueous solution and then with a saturated sodiumchloride solution and dried over anhydrous magnesium sulphate, and thesolvent was distilled off under reduced pressure. The titled compound(66.0 g) having the following physical properties was obtained.

TLC: Rf 0.68 (hexane:ethyl acetate=3:1);

¹H-NMR (CDCl₃): δ 1.62 (6H), 3.69 (3H), 6.91 (2H), 6.96-7.08 (4H), 7.40(2H), 7.65 (1H).

Example 5: Methyl2-{4-[3-(4-fluorophenoxy)-5-nitrophenoxy]phenyl}-2-methylpropanoate

Under an argon atmosphere and at room temperature, to a 500-mLpear-shaped evaporating flask were added the compound prepared inExample 4 (64 g), 4-fluorophenol (40 g) and potassium phosphate (102 g)which were dissolved in DMA (130 mL) before stirring. The solution wasthen heated to 100° C. and stirred for 10 hours. The reaction solutionwas cooled to room temperature, diluted with MTBE (200 mL) and addedwith ice water (400 mL) before stirring. The reaction solution wasfurther washed with MTBE, a 1 N sodium hydroxide aqueous solution andwater. An aqueous layer was extracted twice with MTBE. The organic layerwas combined, washed twice with a 1 N sodium hydroxide aqueous solutionand then with water and a saturated sodium chloride solution and driedover anhydrous magnesium sulphate, and the solvent was distilled offunder reduced pressure. The obtained residue was added with ethanol (104mL), heated and dissolved. To the solution was gradually added hexane(520 mL) and stirred at room temperature to allow precipitation ofsolids. The precipitate was collected by filtration with a Kiriyamafunnel (#5B-ϕ95) and washed with hexane/ethanol (10:1) and the obtainedresidue was dried under reduced pressure at 50° C. The titled compound(54.8 g) having the following physical properties was obtained.

TLC: Rf 0.57 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.60 (6H), 3.68 (3H), 6.91 (1H), 6.91 (1H), 6.98-7.14(4H), 7.36 (1H), 7.39 (1H), 7.40 (1H), 7.46 (1H).

Example 6: Methyl2-{4-[3-amino-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoate

Under an argon atmosphere, to a 500-mL pear-shaped evaporating flask wasadded the compound prepared in Example 5 (53.6 g) to which a mixedsolution of methanol (50 mL) and ethyl acetate (175 mL) was added. Themixture was heated until dissolution, and the flask was purged withargon prior to addition of 5% palladium carbon (10.8 g). The flask wasdegassed and charged with hydrogen gas. The flask was vigorously stirredat room temperature for 3 hours. The reaction system was purged withargon, filtered with celite and washed with ethyl acetate. The obtainedfiltrate was subjected to distillation under reduced pressure to givethe titled compound (43.9 g) having the following physical properties.

TLC: Rf 0.13 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.57 (6H), 3.66 (3H), 3.69 (NH, 2H), 5.97 (1H), 6.02(2H), 6.96 (2H), 6.99 (2H), 7.01 (2H), 7.28 (2H).

Example 7: Methyl2-{4-[3-(4-fluorophenoxy)-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoate

Under an argon atmosphere and at room temperature, to a 500-mLpear-shaped evaporating flask were added the compound prepared inExample 6 (43.9 g) and sodium hydrogen carbonate (18.6 g) which weredissolved in ethyl acetate (111 mL). The solution was cooled to 0° C.and 2,2,2-trichloroethyl chloroformate (15.7 mL) was gradually addeddropwise over 15 minutes so that the internal temperature did not exceed10° C. The solution was then stirred at room temperature for 60 minutes.After elimination of 2,2,2-trichloroethyl chloroformate was confirmed bythin layer chromatography, the reaction solution was added with waterand stirred. The solid was precipitated by addition of hexane. Theprecipitate was collected by filtration with a Kiriyama funnel (#5B-ϕ95)and washed with water and hexane/ethyl acetate (3:1) and the obtainedresidue was dried under reduced pressure at 50° C. The titled compound(58.5 g) having the following physical properties was obtained.

TLC: Rf 0.45 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 1.58 (6H), 3.66 (3H), 4.77 (2H), 6.36 (1H), 6.73 (1H),6.78 (br, 1H), 6.82 (br, 1H), 6.93-7.10 (6H), 7.31 (2H).

Example 8: Methyl2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoate

Under an argon atmosphere and at room temperature, in a 500 mLpear-shaped evaporating flask, the compound prepared in Example 7 (26.6g) was dissolved in DMA (31 mL), added with 4-isobutyl-4-piperidinol(9.53 g) and stirred. The solution was then heated to 90° C. and stirredfor 2 hours. The solution was further added with4-isobutyl-4-piperidinol (1.45 g) and diisopropylethylamine (818 μL) andstirred for 2 hours. The reaction solution was allowed to cool to roomtemperature, diluted with MTBE, and added with ice water to extract anorganic layer. The obtained aqueous layer was extracted with MTBE. Theorganic layer was combined, washed twice with a 1 N hydrochloric acidaqueous solution, three times with a 1 N sodium hydroxide aqueoussolution, with water and with a saturated sodium chloride solution anddried over anhydrous sodium sulphate and the solvent was distilled offunder reduced pressure. The titled compound (24.8 g) having thefollowing physical properties was obtained.

TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

¹H-NMR (CDCl₃): δ 0.97 (6H), 1.05 (1H), 1.41 (2H), 1.50-1.70 (10H),1.75-1.90 (1H), 3.20-3.35 (2H), 3.66 (3H), 3.70-3.80 (2H), 6.25-6.35(2H), 6.71 (1H), 6.81 (1H), 6.90-7.05 (6H), 7.29 (2H).

Example 9:2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

At room temperature, in a 1 L pear-shaped evaporating flask, thecompound prepared in Example 8 (24.8 g) was dissolved in a mixedsolution of methanol (150 mL) and THF (150 mL) and the solution wasstirred. The solution was then heated to 45° C., gradually added with a1 N sodium hydroxide aqueous solution (107 mL) and stirred overnight at45° C. The solution was added with a 2 N sodium hydroxide aqueoussolution (20 mL). After stirring for 1 hour, the solvent was distilledoff under reduced pressure and the solution was further stirred for 1.5hours at 45° C. A 2 N sodium hydroxide aqueous solution (12 mL) wasfurther added and the solution was stirred for 45 minutes at 55° C. Thesolution was cooled to 0° C. and added with ice and a 5 N hydrochloricacid aqueous solution until the reaction system was acidic (pH=2). Thereaction system was diluted with ethyl acetate and extracted. An organiclayer was further washed with a saturated sodium chloride solution andthen dried over anhydrous magnesium sulphate and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=65:35→44:56→30:70) to give thetitled compound (20 g) having the following physical properties.

TLC: Rf 0.53 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃) δ 7.28-7.33 (m, 2H), 6.94-7.01 (m, 4H), 6.89-6.93 (m,2H), 6.80 (t, 1H), 6.61 (t, 1H), 6.25 (t, 1H), 3.60-3.73 (m, 2H),3.12-3.25 (m, 2H), 1.71-1.85 (m, 1H), 1.46-1.59 (m, 10H), 1.34 (d, 2H),0.92 (d, 6H).

Examples 9(1) to 9(64)

The compounds of the following Examples were obtained by carrying outthe processes with the same purposes as Example 4→Example 5→Example6→Example 7→Example 8→Example 9 using 1,3-difluoro-5-nitrobenzene; thecompound prepared in Example 3 or a corresponding phenol derivativethereof; 4-fluorophenol or a corresponding phenol derivative thereof;2,2,2-trichloroethyl chloroformate; and 4-isobutyl-4-piperidinol or acorresponding piperidine derivative thereof.

Example 9(1):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoicAcid

TLC: Rf 0.28 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 8.01 (d, 2H) 7.18-6.99 (m, 6H) 6.94-6.87 (m, 2H) 6.29(t, 1H) 3.90-3.75 (m, 2H) 3.28-3.15 (m, 2H) 1.63-1.47 (m, 4H) 1.45-1.26(m, 7H) 0.87 (t, 6H).

Example 9(2):4-[3-({[4-(4-bromophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoicAcid

TLC: Rf 0.38 (dichloromethane:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (d, 2H), 7.41 (d,2H), 7.24 (t, 2H), 7.15-7.07 (m, 5H), 7.02 (dd, 1H), 6.31 (dd, 1H), 5.18(s, 1H), 3.98-3.94 (m, 2H), 3.17-3.10 (m, 2H), 1.83-1.76 (m, 2H),1.57-1.53 (m, 2H).

Example 9(3):4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.38 (dichloromethane:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (dd, 2H), 7.24 (t,2H), 7.15-7.07 (m, 7H), 7.02 (dd, 1H), 6.31 (dd, 1H), 5.13 (s, 1H),3.98-3.93 (m, 2H), 3.18-3.10 (m, 2H), 1.84-1.77 (m, 2H), 1.59-1.54 (m,2H).

Example 9(4):4-[3-(4-chlorophenoxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.33 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 8.48 (s, 1H), 8.02 (d, 2H), 7.36 (d, 2H), 7.00-7.12(m, 4H), 6.95 (t, 2H), 6.34 (t, 1H), 3.83 (d, 2H), 3.14-3.29 (m, 2H),1.28-1.68 (m, 11H), 0.87 (t, 6H).

Example 9(5):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-methoxyphenoxy)phenoxy]benzoicAcid

TLC: Rf 0.33 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 8.43 (s, 1H), 7.97-8.04 (m, 2H), 7.04 (d, 2H),6.90-7.02 (m, 4H), 6.86-6.89 (m, 1H), 6.85 (t, 1H), 6.15-6.29 (m, 1H),3.78-3.85 (m, 5H), 3.13-3.28 (m, 2H), 1.49-1.71 (m, 4H), 1.23-1.44 (m,7H), 0.87 (t, 6H).

Example 9(6):4-[3-(3,4-difluorophenoxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.37 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃): δ 8.03 (d, 2H), 7.06-7.18 (m, 1H), 7.03 (d, 2H),6.84-6.93 (m, 3H), 6.73-6.81 (m, 1H), 6.53 (br. s., 1H), 6.37-6.41 (m,1H), 3.73-3.83 (m, 2H), 3.22-3.34 (m, 2H), 1.55-1.65 (m, 5H), 1.28-1.42(m, 7H), 0.79-0.90 (m, 6H).

Example 9(7):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-methylphenoxy)phenoxy]benzoicAcid

TLC: Rf 0.24 (dichloromethane:methanol=1:2);

¹H-NMR (CDCl₃): δ 8.02 (d, 2H), 7.14 (d, 2H), 7.02 (d, 2H), 6.97-6.91(m, 3H), 6.72 (t, 1H), 6.42-6.31 (m, 2H), 3.84-3.73 (m, 2H), 3.37-3.14(m, 2H), 2.33 (s, 3H), 1.75-1.50 (m, 5H), 1.44-1.28 (m, 8H), 0.85 (t,6H).

Example 9(8):4-{3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-[4-(trifluoromethyl)phenoxy]phenoxy}benzoicAcid

TLC: Rf 0.26 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.09-7.97 (m, 2H), 7.58 (d, 2H), 7.09 (d, 2H),7.07-7.01 (m, 2H), 6.97 (t, 1H), 6.92 (t, 1H), 6.48 (s, 1H), 6.45 (t,1H), 3.85-3.73 (m, 2H), 3.39-3.17 (m, 2H), 1.65-1.51 (m, 4H), 1.45-1.26(m, 9H), 0.84 (t, 6H).

Example 9(9):2-chloro-4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoicAcid

TLC: Rf 0.33 (chloroform:methanol=5:1);

¹H-NMR (CD₃OD): δ 7.60 (d, 1H), 7.08-6.80 (m, 8H), 6.25 (t, 1H), 3.83(m, 2H), 3.22 (m, 2H), 1.66-1.30 (m, 11H), 0.86 (t, 6H).

Example 9(10):4-[3-(cyclohexyloxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.38 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.97-8.05 (m, 2H), 6.97-7.05 (m, 2H), 6.87 (t, 1H),6.66 (t, 1H), 6.38 (s, 1H), 6.31 (t, 1H), 4.18-4.25 (m, 1H), 3.79 (d,2H), 3.23-3.35 (m, 2H), 1.84-2.00 (m, 2H), 1.69-1.84 (m, 2H), 1.46-1.65(m, 6H), 1.22-1.45 (m, 11H), 0.85 (t, 6H).

Example 9(11):4-[3-(2-chlorophenoxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.25 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.07-7.95 (m, 2H), 7.44 (dd, 1H), 7.30-7.20 (m, 1H),7.15-7.05 (m, 2H), 7.05-6.99 (m, 2H), 6.96 (t, 1H), 6.75 (t, 1H), 6.45(s, 1H), 6.34 (t, 1H), 3.85-3.72 (m, 2H), 3.38-3.14 (m, 2H), 1.65-1.57(m, 4H), 1.45-1.24 (m, 8H), 0.84 (t, 6H).

Example 9(12):4-[3-(3-chlorophenoxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.24 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.11-7.96 (m, 2H), 7.31-7.20 (m, 1H), 7.11-7.02 (m,4H), 6.99 (t, 1H), 6.96-6.89 (m, 1H), 6.83 (t, 1H), 6.43 (s, 1H), 6.41(t, 1H), 3.86-3.74 (m, 2H), 3.39-3.14 (m, 2H), 1.75-1.50 (m, 6H),1.44-1.25 (m, 7H), 0.85 (t, 6H).

Example 9(13):{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}acetic Acid

TLC: Rf 0.36 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.24 (d, 2H), 7.03-6.96 (m, 6H), 6.81 (dd, 1H), 6.65(dd, 1H), 6.40 (brs, 1H), 6.31 (dd, 1H), 3.76-3.72 (m, 2H), 3.62 (s,2H), 3.28-3.20 (m, 2H), 1.60-1.58 (m, 4H), 1.39-1.33 (m, 8H), 0.84 (t,6H).

Example 9(14):4-[3-(2,4-difluorophenoxy)-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.29 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.01 (d, 2H), 7.19-7.06 (m, 1H), 7.06-6.69 (m, 6H),6.51 (br. s., 1H), 6.33 (t, 1H), 3.85-3.65 (m, 2H), 3.35-3.11 (m, 2H),1.67-1.50 (m, 4H), 1.43-1.18 (m, 8H), 0.84 (t, 6H).

Example 9(15):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]-2-hydroxybenzoicAcid

TLC: Rf 0.16 (dichloromethane:methanol:ethanol=100:10:1);

¹H-NMR (CDCl₃): δ 7.48-7.62 (m, 1H), 6.91-7.10 (m, 5H), 6.77-6.87 (m,1H), 6.67 (t, 1H), 6.57 (br. s., 1H), 6.25 (br. s., 1H), 3.55-3.83 (m,2H), 3.03-3.30 (m, 2H), 1.41-1.57 (m, 4H), 1.21-1.40 (m, 7H), 0.81 (t,6H).

Example 9(16):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]-3-fluorobenzoicAcid

TLC: Rf 0.48 (dichloromethane:methanol=8:2);

¹H-NMR (CD₃OD): δ 8.46 (s, 1H), 7.77-7.86 (m, 2H), 7.00-7.20 (m, 5H),6.83-6.91 (m, 2H), 6.25-6.30 (m, 1H), 3.82 (d, 2H), 3.14-3.28 (m, 2H),1.20-1.67 (m, 11H), 0.86 (t, 6H).

Example 9(17):{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]-2-fluorophenyl}aceticAcid

TLC: Rf 0.19 (chloroform:methanol=19:1);

¹H-NMR (CDCl₃): δ 6.54-7.20 (m, 10H), 6.30 (s, 1H), 3.71 (br. s., 2H),3.56 (br. s., 2H), 3.19 (br. s., 2H), 1.13-1.47 (m, 13H), 0.64-0.93 (m,6H).

Example 9(18):4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]benzoicAcid

TLC: Rf 0.22 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 7.95-8.05 (m, 2H), 6.99-7.16 (m, 6H), 6.89-6.90 (m,2H), 6.27 (dd, 1H), 3.77-3.82 (m, 2H), 3.18-3.28 (m, 2H), 1.76-1.93 (m,1H), 1.46-1.65 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).

Example 9(19):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorobenzoyl)phenoxy]benzoicAcid

TLC: Rf 0.25 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.88-7.96 (m, 2H), 7.71-7.80 (m, 2H), 7.40-7.47 (m,2H), 7.02-7.11 (m, 2H), 6.90-6.97 (m, 3H), 3.69-3.73 (m, 2H), 3.11-3.20(m, 2H), 1.45-1.54 (m, 4H), 1.19-1.33 (m, 7H), 0.75 (t, 6H).

Example 9(20):2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.39 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.33 (d, 2H), 6.92-7.05 (m, 6H), 6.77-6.78 (m, 1H),6.65-6.68 (m, 1H), 6.44 (s, 1H), 6.24-6.32 (m, 1H), 3.70-3.77 (m, 2H),3.14-3.31 (m, 2H), 1.52-1.65 (m, 10H), 1.29-1.42 (m, 7H), 0.84 (t, 6H).

Example 9(21):2-chloro-4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]benzoicAcid

TLC: Rf 0.30 (chloroform:methanol=5:1);

¹H-NMR (CDCl₃+CD₃OD): δ 7.69 (d, 1H), 7.20-6.84 (m, 9H), 6.26 (t, 1H),3.80 (m, 2H), 3.23 (m, 2H), 1.87 (m, 1H), 1.66-1.48 (m, 4H), 1.37 (d,2H), 0.95 (d, 6H).

Example 9(22):4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]-2-methylbenzoicAcid

TLC: Rf 0.33 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.81 (d, 1H), 6.96-7.05 (m, 4H), 6.67-6.82 (m, 4H),6.29 (t, 1H), 3.66-3.76 (m, 2H), 3.14-3.25 (m, 2H), 2.46 (s, 3H),1.49-1.62 (m, 4H), 1.23-1.39 (m, 7H), 0.82 (t, 6H).

Example 9(23):4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]-2-methylbenzoicAcid

TLC: Rf 0.70 (chloroform:methanol=5:1);

¹H-NMR (CDCl₃+CD₃OD): δ 7.81 (d, 1H), 7.18-6.78 (m, 8H), 6.24 (t, 1H),3.80 (m, 2H), 3.23 (m, 2H), 2.52 (s, 3H), 1.84 (m, 1H), 1.68-1.48 (m,4H), 1.40 (d, 2H), 0.95 (d, 6H).

Example 9(24):3-fluoro-4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]benzoicAcid

TLC: Rf 0.20 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 7.68-7.77 (m, 2H), 6.98-7.12 (m, 5H), 6.90 (dd, 1H),6.73 (dd, 1H), 6.21 (dd, 1H), 3.76-3.80 (m, 2H), 3.15-3.28 (m, 2H),1.83-1.93 (m, 1H), 1.43-1.69 (m, 4H), 1.37 (d, 2H), 0.96 (d, 6H).

Example 9(25):4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]-2-methoxybenzoicAcid

TLC: Rf 0.47 (dichloromethane:methanol=9:1);

¹H-NMR (CD₃OD): δ 7.87 (d, 1H), 7.03-7.13 (m, 4H), 6.88-6.94 (m, 2H),6.76 (d, 1H), 6.58 (dd, 1H), 6.30 (dd, 1H), 3.85 (s, 1H), 3.76-3.86 (m,2H), 3.19-3.28 (m, 2H), 1.81-1.90 (m, 1H), 1.48-1.64 (m, 4H), 1.38 (d,2H), 0.96 (d, 6H).

Example 9(26):2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoicAcid

TLC: Rf 0.31 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.24 (d, 2H), 6.96-7.05 (m, 4H), 6.92 (d, 2H), 6.82(t, 1H), 6.60-6.66 (m, 1H), 6.27 (t, 1H), 3.54-3.75 (m, 3H), 3.11-3.26(m, 2H), 1.70-1.88 (m, 1H), 1.48-1.60 (m, 4H), 1.44 (d, 3H), 1.36 (d,2H), 0.94 (d, 6H).

Example 9(27):{2-fluoro-4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}aceticAcid

TLC: Rf 0.17 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.10 (t, 1H), 6.93-7.02 (m, 4H), 6.87 (s, 1H),6.59-6.73 (m, 3H), 6.27 (s, 1H), 3.61-3.75 (m, 2H), 3.47 (br. s., 2H),3.08-3.26 (m, 2H), 1.77 (dquin, 1H), 1.38-1.59 (m, 4H), 1.32 (d, 2H),0.91 (d, 6H).

Example 9(28):{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}aceticAcid

TLC: Rf 0.17 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 8.38 (s, 1H), 7.27 (d, 2H), 7.01-7.12 (m, 4H),6.94-7.00 (m, 2H), 6.81 (dq, 2H), 6.21 (t, 1H), 3.75-3.84 (m, 2H), 3.59(s, 2H), 3.16-3.29 (m, 2H), 1.77-1.93 (m, 1H), 1.45-1.64 (m, 4H), 1.38(d, 2H), 0.97 (d, 6H).

Example 9(29):2-fluoro-4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.34 (chloroform:methanol=4:1);

¹H-NMR (CD₃OD): δ 7.91 (t, 1H), 7.53-7.47 (m, 2H), 7.16-6.95 (m, 8H),6.88-6.76 (m, 2H), 6.33 (t, 1H), 4.08-3.97 (m, 2H), 3.40-3.30 (m, 2H),2.07-1.94 (m, 2H), 1.77-1.67 (m, 2H).

Example 9(30):{2-fluoro-4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}aceticAcid

TLC: Rf 0.41 (chloroform:methanol=4:1);

¹H-NMR (CD₃OD): δ 7.53-7.46 (m, 2H), 7.28 (t, 1H), 7.15-7.00 (m, 6H),6.91-6.87 (m, 2H), 6.83-6.76 (m, 2H), 6.28 (t, 1H), 4.06-3.97 (m, 2H),3.63 (s, 2H), 3.38-3.30 (m, 2H), 2.06-1.93 (m, 2H), 1.77-1.68 (m, 2H).

Example 9(31):2-{4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}propanoicAcid

TLC: Rf 0.32 (chloroform:methanol=9:1);

¹H-NMR (CD₃OD): δ 7.41-7.56 (m, 2H), 7.24-7.36 (m, 2H), 6.91-7.15 (m,8H), 6.85 (t, 1H), 6.80 (t, 1H), 6.21 (t, 1H), 4.00 (d, 2H), 3.69 (q,1H), 3.19-3.41 (m, 2H), 1.98 (td, 2H), 1.71 (d, 2H), 1.44 (d, 3H).

Example 9(32):4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]benzoicAcid

TLC: Rf 0.63 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.97 (d, 2H), 7.18-7.06 (m, 1H), 7.02-6.75 (m, 6H),6.28 (m, 1H), 3.73 (m, 2H), 3.30-3.19 (m, 2H), 1.89-1.75 (m, 1H),1.65-1.43 (m, 4H), 1.38 (d, 2H) 1.29-1.23 (m, 1H), 0.95 (d, 6H).

Example 9(33):{4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}aceticAcid

TLC: Rf 0.63 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.22 (d, 2H), 7.10 (td, 1H), 7.00-6.79 (m, 5H), 6.60(t, 1H), 6.27 (t, 1H), 3.70 (m, 2H), 3.52 (s, 2H), 3.28-3.13 (m, 2H),1.90-1.73 (m, 1H), 1.64-1.47 (m, 4H), 1.37 (d, 2H), 0.95 (d, 6H).

Example 9(34):2-chloro-4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]benzoicAcid

TLC: Rf 0.68 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.70 (d, 2H), 7.13 (m, 1H), 7.03-6.81 (m, 5H), 6.72(t, 1H), 6.27 (t, 1H), 3.74 (m, 2H), 3.31-3.12 (m, 2H), 1.92-1.72 (m,1H), 1.48-1.65 (m, 4H), 1.33-1.42 (m, 2H), 1.21-1.30 (m, 1H), 0.86-1.01(d, 6H).

Example 9(35):{4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]-2-fluorophenyl}acetic Acid

TLC: Rf 0.56 (dichloromethane:methanol=8:2);

¹H-NMR (CD₃OD): δ 7.16-7.33 (m, 2H), 7.11 (ddd, 1H), 6.92-7.03 (m, 1H),6.85 (s, 2H), 6.72-6.82 (m, 2H), 6.24 (t, 1H), 3.80 (dt, 2H), 3.62 (s,2H), 3.16-3.29 (m, 2H), 1.77-1.95 (m, 1H), 1.43-1.67 (m, 4H), 1.38 (d,2H) 0.97 (d, 6H).

Example 9(36):2-{4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoicAcid

TLC: Rf 0.72 (dichloromethane:methanol=8:2);

¹H-NMR (CD₃OD): δ 7.31 (d, 2H), 7.19 (td, 1H), 7.06-7.15 (m, 1H),6.91-7.02 (m, 3H), 6.81 (t, 1H), 6.78 (t, 1H), 6.18 (t, 1H), 3.74-3.84(m, 2H), 3.69 (q, 1H), 3.16-3.29 (m, 2H), 1.75-1.94 (m, 1H), 1.48-1.64(m, 4H), 1.45 (d, 3H), 1.38 (d, 2H), 0.97 (d, 6H).

Example 9(37):4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.58 (chloroform:methanol=5:1);

¹H-NMR (CD₃OD): δ 7.98 (d, 1H), 7.18-6.98 (m, 6H), 6.88 (d, 2H), 6.25(m, 1H), 3.90 (m, 2H), 3.11 (m, 2H), 1.66-1.40 (m, 7H), 1.22-1.10 (m,2H), 0.86 (t, 6H).

Example 9(38):(2E)-3-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}acrylicAcid

TLC: Rf 0.31 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.49 (dd, 1H), 7.37-7.45 (m, 2H), 6.89-7.01 (m, 6H),6.75-6.81 (m, 2H), 6.21-6.33 (m, 2H), 3.61-3.73 (m, 2H), 3.09-3.23 (m,2H), 1.68-1.82 (m, 1H), 1.41-1.59 (m, 4H), 1.31 (dd, 2H), 0.88 (dd, 6H).

Example 9(39):4-[3-(2,4-difluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.68 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.99 (d, 2H), 7.50-7.35 (m, 2H), 7.19-6.80 (m, 9H),6.30 (t, 1H), 3.94 (m, 2H), 3.39-3.24 (m, 2H), 1.98 (m, 2H), 1.75 (d,2H).

Example 9(40):3-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoicAcid

TLC: Rf 0.40 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.13 (d, 2H), 6.95-7.05 (m, 4H), 6.90 (d, 2H),6.72-6.77 (m, 1H), 6.62-6.67 (m, 1H), 6.24-6.29 (m, 1H), 3.62-3.74 (m,2H), 3.15-3.25 (m, 2H), 2.80-2.93 (m, 2H), 2.48-2.59 (m, 2H), 1.80(dquin, 1H), 1.43-1.62 (m, 4H), 1.35 (d, 2H), 0.93 (d, 6H).

Example 9(41):{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}aceticAcid

TLC: Rf 0.58 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.22 (d, 2H), 7.06-6.90 (m, 6H), 6.83 (t, 1H), 6.63(t, 1H), 6.30 (t, 1H), 3.79 (m, 2H), 3.56 (s, 2H), 3.26-3.01 (m, 2H),1.67-1.41 (m, 6H), 1.34-1.08 (m, 3H), 1.06-0.84 (m, 7H).

Example 9(42):2-chloro-4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.51 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.80 (m, 1H), 7.07-6.95 (m, 5H), 6.93-6.72 (m, 3H),6.30 (t, 1H) 3.82 (m, 2H) 3.28-3.03 (m, 2H), 1.73-1.45 (m, 6H),1.34-1.11 (m, 3H), 1.06-0.83 (m, 7H).

Example 9(43):2-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}-2-ethylpropanoicAcid

TLC: Rf 0.56 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.39-7.29 (m, 2H), 7.07-6.92 (m, 6H), 6.81 (t, 1H),6.65 (t, 1H), 6.29 (t, 1H), 3.79 (m, 2H), 3.27-3.08 (m, 2H), 1.66-1.42(m, 12H), 1.33-1.10 (m, 3H), 1.05-0.87 (m, 7H).

Example 9(44):4-[3-(3,4-difluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.76 (dichloromethane:methanol=3:1);

¹H-NMR (CD₃OD): δ 8.49 (s, 1H), 8.07-7.97 (m, 2H), 7.32-7.23 (m, 1H),7.11-6.92 (m, 5H), 6.90-6.80 (m, 1H), 6.35 (t, 1H), 3.95-3.80 (m, 2H),3.27-3.07 (m, 2H), 1.70-1.44 (m, 6H), 1.28-1.08 (m, 2H), 1.06-0.91 (m,7H).

Example 9(45):2-chloro-4-[3-(3,4-difluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]benzoicAcid

TLC: Rf 0.51 (dichloromethane:methanol=3:1);

¹H-NMR (CD₃OD): δ 8.52 (s, 1H), 7.92 (d, 1H), 7.31-7.19 (m, 1H), 7.10(d, 1H), 7.07-6.95 (m, 4H), 6.92-6.81 (m, 1H), 6.38 (t, 1H), 4.00-3.80(m, 2H), 3.26-3.08 (m, 2H), 1.73-1.46 (m, 6H), 1.29-1.06 (m, 2H),1.05-0.90 (m, 7H).

Example 9(46):2-{4-[3-(3,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.32 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.43-7.35 (m, 2H), 7.31-7.16 (m, 1H), 7.04-6.91 (m,3H), 6.90-6.86 (m, 1H), 6.86-6.78 (m, 2H), 6.25 (t, 1H), 3.90-3.70 (m,2H), 3.28-3.14 (m, 2H), 1.95-1.75 (m, 1H) 1.66-1.45 (m, 10H), 1.39 (d,2H), 0.97 (d, 6H).

Example 9(47):4-[3-(3,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]-3-fluorobenzoicAcid

TLC: Rf 0.52 (dichloromethane:methanol=3:1);

¹H-NMR (CD₃OD): δ 8.47 (s, 1H), 7.88-7.78 (m, 2H), 7.34-7.09 (m, 2H),7.05-6.94 (m, 1H), 6.94-6.89 (m, 2H), 6.89-6.79 (m, 1H), 6.33 (t, 1H),3.86-3.69 (m, 2H), 3.28-3.16 (m, 2H), 1.93-1.72 (m, 1H), 1.67-1.43 (m,4H), 1.38 (d, 2H), 0.96 (d, 6H).

Example 9(48):{4-[3-(3,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]-2-fluorophenyl}aceticAcid

TLC: Rf 0.72 (dichloromethane:methanol=3:1);

¹H-NMR (CD₃OD): δ 8.45 (s, 1H), 7.34-7.15 (m, 2H), 7.05-6.94 (m, 1H),6.93-6.87 (m, 2H), 6.86-6.73 (m, 3H), 6.30 (t, 1H), 3.88-3.72 (m, 2H),3.62 (d, 2H), 3.27-3.17 (m, 2H), 1.92-1.75 (m, 1H), 1.67-1.44 (m, 4H),1.38 (d, 2H), 0.96 (d, 6H).

Example 9(49):2-{4-[3-(3,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoicAcid

TLC: Rf 0.29 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 8.42 (s, 1H), 7.36-7.29 (m, 2H), 7.29-7.17 (m, 1H),7.05-6.90 (m, 3H), 6.89-6.78 (m, 3H), 6.25 (t, 1H), 3.87-3.76 (m, 2H)3.71 (q, 1H), 3.28-3.14 (m, 2H), 1.96-1.76 (m, 1H), 1.66-1.50 (m, 4H),1.45 (d, 3H), 1.39 (d, 2H), 0.97 (d, 6H).

Example 9(50):{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenoxy}aceticAcid

TLC: Rf 0.29 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃): δ 7.01-6.89 (m, 4H), 6.85-6.66 (m, 5H), 6.58 (m, 1H),6.18 (m, 1H), 4.37-4.20 (m, 2H), 3.69 (m, 2H), 3.14 (m, 2H), 1.59-1.21(m, 11H), 0.72-0.87 (m, 6H).

Example 9(51):2-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-methylbutyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.28 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.33-7.39 (m, 2H), 6.96-7.06 (m, 6H), 6.78-6.81 (m,1H), 6.69 (t, 1H), 6.38 (s, 1H), 6.30-6.32 (m, 1H), 3.71-3.77 (m, 2H),3.20-3.31 (m, 2H), 1.53-1.64 (m, 8H), 1.43-1.53 (m, 4H), 1.19-1.31 (m,4H), 0.90 (d, 6H).

Example 9(52):2-(4-{3-[(4,4-difluorocyclohexyl)oxy]-5-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy}phenyl)-2-methylpropanoicAcid

TLC: Rf 0.45 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.29 (d, 2H), 6.97-6.84 (m, 3H), 6.63 (m, 1H), 6.41(m, 1H), 6.27 (m, 1H), 4.43 (m, 1H), 3.80-3.63 (m, 2H), 3.32-3.13 (m,2H), 2.10-1.71 (m, 7H), 1.21-1.53 (m, 18H), 0.90-0.75 (t, 6H).

Example 9(53):2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(2-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.40 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.33 (d, 2H), 7.16-7.03 (m, 3H), 6.96 (d, 2H),6.79-6.64 (m, 2H), 6.42 (m, 1H), 6.35-6.23 (m, 1H), 3.70 (m, 2H),3.32-3.10 (m, 2H), 1.62-1.52 (m, 8H), 1.46-1.20 (m, 4H), 0.93-0.69 (t,6H).

Example 9(54):2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(2-methylphenoxy)phenoxy]phenyl}-2-ethylpropanoicAcid

TLC: Rf 0.45 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.31-7.17 (m, 2H), 7.15-6.98 (m, 2H), 6.95-6.81 (m,4H), 6.62 (m, 1H), 6.58 (m, 1H), 6.24 (m, 1H), 3.64 (m, 2H), 3.10 (m,2H), 2.19 (s, 3H), 1.47 (m, 4H), 1.36-1.18 (m, 8H), 0.88-0.73 (t, 6H).

Example 9(55):2-{4-[3-{[(4-cyclopentyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.49 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.32 (m, 2H), 7.08-6.90 (m, 6H), 6.76 (m, 1H), 6.66(m, 1H), 6.48 (m, 1H), 6.29 (m, 1H), 3.74 (m, 2H), 3.18 (m, 2H), 2.11(m, 4H), 1.78 (m, 1H), 1.74-1.50 (m, 6H), 1.57 (s, 6H), 1.33 (m, 2H).

Example 9(56):2-{4-[3-{[(4-cyclohexyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.33 (chloroform:methanol=19:1);

¹H-NMR (CD₃OD): δ 1.00-1.30 (m, 6H), 1.49-1.71 (m, 11H), 1.76-1.86 (m,4H), 3.10-3.22 (m, 2H), 3.84-3.96 (m, 2H), 6.19 (t, 1H), 6.78-6.84 (m,2H), 6.95-7.12 (m, 6H), 7.35-7.41 (m, 2H), 8.36 (brs, 1H).

Example 9(57):2-{3-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenoxy}-2-methylpropanoicAcid

TLC: Rf 0.35 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.21 (t, 1H), 7.04 (d, 4H), 6.82 (t, 1H), 6.71 (d,1H), 6.69 (d, 1H), 6.50 (t, 1H), 6.46 (t, 1H), 6.33-6.29 (m, 2H), 3.74(s, 2H), 3.36-3.21 (m, 2H), 2.09 (s, 1H), 1.82 (dt, 1H), 1.63-1.55 (m,10H), 1.40 (d, 2H), 0.96 (d, 6H).

Example 9(58):2-{3-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic Acid

TLC: Rf 0.41 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.34-7.28 (m, 1H), 7.18-7.10 (m, 2H), 7.05-6.99 (m,4H), 6.92 (dd, 1H), 6.68-6.65 (m, 1H), 6.60 (t, 1H), 6.40 (s, 1H), 6.35(t, 1H), 3.77-3.66 (m, 2H), 3.30-3.17 (m, 2H), 1.83 (dt, 1H), 1.62-1.55(m, 10H), 1.40 (d, 2H), 0.97 (d, 6H).

Example 9(59):2-[4-(3-[(4,4-difluorocyclohexyl)oxy]-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy)phenyl]-2-methylpropanoicAcid

TLC: Rf 0.38 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.41-7.33 (m, 2H), 7.01-6.91 (m, 2H), 6.91-6.84 (m,1H), 6.63 (t, 1H), 6.25 (t, 1H), 4.54-4.40 (m, 1H), 3.90-3.73 (m, 2H),3.28-3.16 (m, 2H), 2.19-1.75 (m, 9H), 1.55 (s, 6H), 1.68-1.45 (m, 4H),1.40 (d, 2H), 0.98 (d, 6H).

Example 9(60):2-{3-fluoro-4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.40 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.29-7.22 (m, 1H), 7.22-7.16 (m, 1H), 7.14-6.98 (m,5H), 6.85-6.81 (m, 1H), 6.75 (t, 1H), 6.17 (t, 1H), 3.86-3.71 (m, 2H),3.29-3.15 (m, 2H), 1.95-1.73 (m, 1H), 1.55 (s, 6H), 1.64-1.45 (m, 4H),1.39 (d, 2H), 0.97 (d, 6H).

Example 9(61):1-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenoxy}cyclopropanecarboxylic Acid

TLC: Rf 0.31 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.06-6.86 (m, 8H), 6.69 (t, 1H), 6.58 (s, 1H), 6.53(t, 1H), 6.28 (t, 1H), 3.70 (dt, 2H), 3.26-3.13 (m, 2H), 1.90-1.75 (m,1H), 1.69-1.62 (m, 2H), 1.61-1.53 (m, 4H), 1.42-1.33 (m, 4H), 0.97 (d,6H).

Example 9(62):N-{3-(4-fluorophenoxy)-5-[(6-isopropyl-3-pyridinyl)oxy]phenyl}-4-hydroxy-4-isobutyl-1-piperidinecarboxamide

TLC: Rf 0.53 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.32 (d, 1H), 7.31-7.27 (m, 1H), 7.15 (d, 1H),7.07-6.98 (m, 4H), 6.80-6.75 (m, 2H), 6.34 (s, 1H), 6.29 (t, 1H),3.81-3.70 (m, 2H), 3.34-3.23 (m, 2H), 3.12-2.96 (m, 1H), 1.85 (dt, 1H),1.64-1.59 (m, 4H), 1.42 (d, 2H), 1.30 (d, 6H), 1.07 (s, 1H), 0.98 (d,6H).

Example 9(63):2-{4-[3-{[(4-cyclopentyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenoxy}-2-methylpropanoicAcid

TLC: Rf 0.13 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.37 (s, 1H), 6.99-6.89 (m, 4H), 6.83 (s, 4H),6.77-6.71 (m, 1H), 6.62-6.56 (m, 1H), 6.19-6.12 (m, 1H), 3.77-3.66 (m,2H), 3.18-3.02 (m, 2H), 1.83-1.68 (m, 1H), 1.62-1.38 (m, 16H), 1.35-1.23(m, 2H).

Example 9(64):2-{4-[3-{[(4-cyclopentyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]-2-fluorophenyl}-2-methylpropanoicAcid

TLC: Rf 0.47 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.30-7.21 (m, 1H), 7.08-6.97 (m, 4H), 6.84 (t, 1H),6.81-6.65 (m, 3H), 6.50 (s, 1H), 6.34-6.31 (m, 1H), 3.85-3.74 (m, 2H),3.30-3.17 (m, 2H), 1.93-1.79 (m, 1H), 1.73-1.49 (m, 16H), 1.42-1.31 (m,2H).

Example 10: 1-fluoro-3-(4-fluorophenoxy)-5-nitrobenzene

Under an argon atmosphere and at room temperature, in a 500-mLpear-shaped evaporating flask, 4-fluorophenol (18.5 g) and1,3-difluoro-5-nitrobenzene (25.0 g) were dissolved in DMA (300 mL). Thereaction system was added with cesium carbonate (15.3 g) and stirred.The reaction system was then heated to 50° C., stirred for 3 hours, thenheated to 65° C., stirred for 1 hour and further heated to 85° C. andstirred for 1 hour. The reaction solution was allowed to cool to roomtemperature, diluted with ethyl acetate and added with water to extractan organic layer. The aqueous layer was added with ethyl acetate toextract an organic layer. The organic layer was combined and washed withwater and a saturated sodium chloride solution and the solvent was thendistilled off under reduced pressure to give the titled compound (35.0g) having the following physical properties.

TLC: Rf 0.83 (hexane:ethyl acetate=5:1);

¹H-NMR (CDCl₃): δ 6.98 (dt, J=9.3, 2.3 Hz, 1H), 7.03-7.18 (m, 4H), 7.56(td, J=2.1, 1.1 Hz, 1H), 7.62 (dt, J=8.1, 2.2 Hz, 1H).

Example 11: 1-(4-fluorophenoxy)-3-(4-iodophenoxy)-5-nitrobenzene

At room temperature, to a 300-mL three-neck flask were added4-iodophenol (44.4 g) and further the compound prepared in Example 10(34.9 g) dissolved in DMA (140 mL) and potassium phosphate (59.2 g) andthe flask was purged with argon. The reaction solution was heated to105° C. and stirred for 7 hours. The reaction solution was allowed tocool to room temperature, diluted with ethyl acetate and added withwater to extract an organic layer. The organic layer was washed twicewith water, twice with 1 N sodium hydroxide and with a saturated sodiumchloride solution and then dried over anhydrous sodium sulphate and thesolvent was distilled off under reduced pressure. The resulting residuewas added with a seed crystal (5 mg) and the solid was precipitatedunder reduced pressure. The solid was added with hexane (300 mL),stirred and left to stand at room temperature to precipitate the solid.The solid was collected by filtration with a Kiriyama funnel and washedwith hexane. The resulting residue was dried under reduced pressure at60° C. to give the titled compound (53.1 g). The filtrate was subjectedto silica gel column chromatography (hexane:MTBE=99:1→95:5) to give apale yellow oily substance. Re-crystallization was carried out with amixed solvent of hexane and MTBE, and the titled compound (14.4 g) wasobtained after filtration with a Kiriyama funnel and washing withhexane. The titled compound having the following physical properties wasobtained at a total amount of 67.5 g.

TLC: Rf 0.31 (hexane:ethyl acetate=10:1);

¹H-NMR (CDCl₃): δ 6.81-6.87 (m, 2H), 6.91 (dd, J=2.1 Hz, 1H), 7.02-7.14(m, 4H), 7.42-7.45 (m, 2H), 7.68-7.73 (m, 2H).

Example 12: Methyl1-{4-[3-(4-bromophenoxy)-5-nitrophenoxy]phenyl}cyclopropanecarboxylate

Under an argon atmosphere and at room temperature, to a solution of zinc(87 mg) in dimethoxyethane (DME) (1.0 mL) in a 100-mL three-neck flaskwere added sequentially lithium chloride (37.6 mg) andchlorotrimethylsilane (TMSCl) (11.3 μL). The mixture was heated to 75°C., added dropwise with methyl 1-bromocyclopropane carboxylate andfurther stirred at 75° C. for 2 hours (this solution is referred to asthe solution 1). Under an argon atmosphere and at room temperature,N-methyl-2-pyrrolidone (NMP) (1.0 mL) was added, degassed and chargedwith argon. Bis(tri-tert-butylphosphine)palladium (0) (Pd(t-Bu₃P)₂) (23mg) was added thereto, stirred for 10 minutes before addition of thecompound prepared in Example 11 (200 mg). The mixture was heated to 95°C. and the solution 1 prepared as above was added dropwise over 30minutes. The mixture was further stirred at 95° C. for 1.5 hours. Thereaction solution was allowed to cool, diluted with ethyl acetate andfiltered with celite. The filtrate was washed with water and a saturatedsodium chloride solution and dried over anhydrous sodium sulphate andthe solvent was distilled off under reduced pressure. The solid wasfiltered, the resulting residue was purified by silica gelchromatography (hexane:ethyl acetate=90:10→80:20→50:50→0:100) to givethe titled compound (143 mg) having the following physical properties.

TLC: Rf 0.42 (hexane:ethyl acetate=4:1).

Example 13:1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylicAcid

The titled compound (12.0 g) having the following physical propertieswas obtained by carrying out the processes with the same purposes asExample 6→Example 7→Example 8→Example 9 using the compound prepared inExample 12 (22.4 g), 2,2,2-trichloroethyl chloroformate and4-(2-ethylbutyl)-4-piperidinol in the place of 4-isobutyl-4-piperidinol.

TLC: Rf 0.32 (chloroform:ethanol=20:1);

¹H-NMR (CDCl₃) δ 7.30-7.25 (m, 2H), 7.05-6.97 (m, 3H), 6.96-6.90 (m,2H), 6.88 (t, 1H), 6.65 (t, 1H), 6.30 (t, 1H), 3.81 (m, 2H), 3.25-3.09(m, 2H), 1.69-1.43 (m, 8H), 1.23-1.10 (m, 5H), 1.07-0.88 (m, 7H).

Examples 13(1) to 13(8)

The compounds of the following Examples were obtained by carrying outthe processes with the same purposes as Example 10→Example 11→Example12→Example 13 using 1,3-difluoro-5-nitrobenzene; 4-iodophenol or acorresponding phenol derivative instead thereof; 4-fluorophenol or acorresponding phenol derivative instead thereof; 2,2,2-trichloroethylchloroformate; methyl 1-bromocyclopropane carboxylate or a correspondingbromide instead thereof; and 4-isobutyl-4-piperidinol or a correspondingpiperidine derivative instead thereof.

Example 13(1):1-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.30 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.29-7.32 (m, 2H), 7.01 (d, 4H), 6.88-6.97 (m, 3H),6.55-6.61 (m, 1H), 6.31-6.32 (m, 1H), 3.74 (d, 2H), 3.13-3.20 (m, 2H),1.51-1.58 (m, 4H), 1.40-1.45 (m, 2H), 1.27-1.39 (m, 7H), 0.97 (m, 2H),0.84 (t, 6H).

Example 13(2):1-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.16 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.24-7.29 (m, 2H), 6.95-7.02 (m, 4H), 6.91 (d, 2H),6.85 (t, 1H), 6.60 (t, 1H), 6.27 (t, 1H), 3.62-3.75 (m, 2H), 3.13-3.27(m, 2H), 1.79 (dquin, 1H), 1.39-1.64 (m, 6H), 1.34 (d, 2H), 1.06-1.13(m, 2H), 0.92 (d, 6H).

Example 13(3):1-{4-[3-(3,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.47 (ethyl acetate:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.39-7.30 (m, 2H), 7.31-7.16 (m, 1H), 7.04-6.92 (m,3H), 6.88 (t, 1H), 6.86-6.81 (m, 2H), 6.26 (t, 1H), 3.90-3.75 (m, 2H),3.28-3.16 (m, 2H), 1.95-1.75 (m, 1H), 1.67-1.45 (m, 6H), 1.39 (d, 2H),1.22-1.13 (m, 2H), 0.97 (d, 6H).

Example 13(4):1-{4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.38 (chloroform:methanol=9:1);

¹H-NMR (CD₃OD): δ 7.43-7.57 (m, 2H), 7.28-7.39 (m, 2H), 6.91-7.16 (m,8H), 6.86 (t, 1H), 6.77-6.84 (m, 1H), 6.22 (t, 1H), 4.00 (d, 2H),3.25-3.41 (m, 2H), 1.88-2.07 (m, 2H), 1.71 (d, 2H), 1.48-1.63 (m, 2H),1.07-1.24 (m, 2H).

Example 13(5):1-{4-[3-(2,4-difluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxylic Acid

TLC: Rf 0.62 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CDCl₃) δ 7.35-7.22 (m, 2H), 7.10 (td, 1H), 6.99-6.81 (m, 5H),6.62 (t, 1H), 6.28 (t, 1H), 3.72 (m, 2H), 3.30-3.16 (m, 2H), 1.90-1.70(m, 1H), 1.67-1.44 (m, 6H), 1.38 (d, 2H), 1.15-1.07 (m, 2H), 0.95 (d,6H).

Example 13(6):1-{2-fluoro-4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.32 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.11-7.20 (m, 1H), 6.95-7.07 (m, 4H), 6.88 (t, 1H),6.60-6.74 (m, 3H), 6.28 (t, 1H), 3.63-3.76 (m, 2H), 3.12-3.27 (m, 2H),1.73-1.86 (m, 1H), 1.49-1.65 (m, 6H), 1.36 (d, 2H), 1.06-1.14 (m, 2H),0.93 (d, 6H).

Example 13(7):1-{4-[3-{[(4-cyclopentyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenoxy}cyclopropanecarboxylicAcid

TLC: Rf 0.15 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.07-6.84 (m, 8H), 6.73 (s, 1H), 6.60-6.50 (m, 2H),6.28 (t, 1H), 3.80-3.69 (m, 2H), 3.24-3.10 (m, 2H), 1.91-1.76 (m, 1H),1.70-1.47 (m, 12H), 1.41-1.31 (m, 4H).

Example 13(8):1-{3-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenoxy}cyclopropanecarboxylic Acid

TLC: Rf 0.16 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.26-7.21 (m, 1H), 7.07-7.01 (m, 4H), 6.77-6.64 (m,4H), 6.48-6.43 (m, 1H), 6.40-6.33 (m, 1H), 6.33-6.24 (m, 1H), 3.79-3.66(m, 2H), 3.35-3.20 (m, 2H), 1.82 (dt, 1H), 1.63-1.51 (m, 6H), 1.39 (d,2H), 1.33-1.25 (m, 2H), 0.96 (d, 6H).

Example 14: N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

The titled compound having the following physical properties wasobtained by carrying out the processes with the same purposes as Example10→Example 11→Example 6→Example 7→Example 8 using1,3-difluoro-5-nitrobenzene; a corresponding phenol derivative in theplace of 4-iodophenol; 4-fluorophenol; 2,2,2-trichloroethylchloroformate; and 4-(2-ethylbutyl)-4-piperidinol in the place of4-isobutyl-4-piperidinol.

TLC: Rf 0.59 (ethyl acetate);

¹H-NMR (CDCl₃): δ 7.74 (d, 2H), 6.99-7.08 (m, 6H), 6.79 (s, 1H), 6.83(s, 1H), 6.62 (s, 1H), 6.33 (t, 1H), 3.76 (d, 2H), 3.11-3.36 (m, 2H),1.25-1.62 (m, 11H), 1.15 (s, 1H), 0.78-0.94 (m, 6H).

Examples 14(1) to 14(30)

The compounds of the following Examples were obtained by carrying outthe processes with the same purposes as Example 10→Example 11→Example6→Example 7→Example 8 using 1,3-difluoro-5-nitrobenzene; a correspondingphenol derivative in the place of 4-iodophenol; 4-fluorophenol or acorresponding phenol derivative instead thereof; 2,2,2-trichloroethylchloroformate; and a corresponding piperidine derivative in the place of4-isobutyl-4-piperidinol.

Example 14(1):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(methylsulphonyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.34 (dichloromethane:methanol=30:1);

¹H-NMR (CDCl₃): δ 7.79-7.94 (m, 2H), 6.90-7.17 (m, 7H), 6.77 (t, 1H),6.42 (s, 1H), 6.29-6.39 (m, 1H), 3.77 (d, 2H), 3.18-3.38 (m, 2H), 3.04(s, 3H), 1.19-1.66 (m, 11H), 1.06 (s, 1H), 0.75-0.92 (m, 6H).

Example 14(2):5-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]-2-pyridinecarboxamide

TLC: Rf 0.31 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 8.30 (d, 1H), 8.14 (d, 1H), 7.68 (d, 1H), 7.38 (dd,1H), 7.11-6.91 (m, 5H), 6.77 (t, 1H), 6.45 (s, 1H), 6.34 (t, 1H) 5.52(br. s., 1H), 3.85-3.72 (m, 2H), 3.40-3.18 (m, 2H), 1.69-1.52 (m, 4H),1.47-1.20 (m, 7H), 1.06 (s, 1H), 0.85 (t, 6H).

Example 14(3):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(4-chlorophenyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.41 (dichloromethane:methanol=9:1);

¹H-NMR (CDCl₃+CD₃OD): δ 7.78 (m, 2H), 7.41-7.29 (m, 6H), 7.06-7.01 (m,4H), 6.88-6.82 (m, 2H), 6.33 (t, 1H), 3.94 (m, 2H), 3.33 (m, 2H), 1.95(m, 2H), 1.72 (m, 2H).

Example 14(4):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(4-fluorophenyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.39 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃+CD₃OD): δ 7.78 (m, 2H), 7.45-7.40 (m, 4H), 7.06-6.85 (m,7H), 6.89-6.84 (m, 2H), 6.33 (t, 1H), 3.94 (m, 2H), 3.33 (m, 2H), 1.95(m, 2H), 1.72 (m, 2H).

Example 14(5):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[(3-methyl-4-pyridinyl)oxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.45 (ethyl acetate:methanol=20:1);

¹H-NMR (CDCl₃): δ 8.36 (br. s., 1H), 8.28 (d, 1H), 7.09-6.95 (m, 4H),6.91 (t, 1H), 6.80 (t, 1H), 6.67 (d, 1H), 6.46 (s, 1H), 6.32 (t, 1H)3.87-3.72 (m, 2H), 3.36-3.16 (m, 2H), 2.26 (s, 3H) 1.79-1.46 (m, 4H),1.46-1.21 (m, 7H) 1.11 (br. s., 1H), 0.85 (t, 6H).

Example 14(6):N-{3-[(2,6-dimethyl-3-pyridinyl)oxy]-5-(4-fluorophenoxy)phenyl}-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.17 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 7.16 (d, 1H), 7.09-6.92 (m, 5H), 6.72 (t, 1H), 6.63(t, 1H), 6.35 (s, 1H), 6.20 (t, 1H), 3.83-3.70 (m, 2H), 3.35-3.17 (m,2H), 2.51 (s, 3H), 2.42 (s, 3H), 1.67-1.55 (m, 4H), 1.44-1.27 (m, 7H),1.04 (s, 1H), 0.85 (t, 6H).

Example 14(7):4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-(4-sulphamoylphenoxy)phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.36 (hexane:ethyl acetate=2:1);

¹H-NMR (DMSO-d₆): δ 8.57 (s, 1H), 7.81 (d, 2H), 7.31 (s, 2H), 7.27-7.09(m, 6H), 7.05 (dd, 1H), 6.99 (dd, 1H), 6.30 (dd, 1H), 4.08 (s, 1H),3.74-3.69 (m, 2H), 3.11-3.03 (m, 2H), 1.46-1.24 (m, 11H), 0.78 (t, 6H).

Example 14(8):4-(4-bromophenyl)-N-[3-(4-fluorophenoxy)-5-(4-sulphamoylphenoxy)phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.27 (hexane:ethyl acetate=1:2);

¹H-NMR (DMSO-d₆): δ 8.64 (s, 1H), 7.82 (d, 2H), 7.48 (d, 2H), 7.41 (d,2H), 7.32 (s, 2H), 7.27-7.10 (m, 6H), 7.08 (dd, 1H), 7.02 (dd, 1H), 6.32(dd, 1H), 5.18 (s, 1H), 3.98-3.94 (m, 2H), 3.18-3.10 (m, 2H), 1.83-1.76(m, 2H), 1.58-1.53 (m, 2H).

Example 14(9):4-(4-bromophenyl)-N-{3-(4-fluorophenoxy)-5-[4-(methylsulphonyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 7.87 (d, 2H), 7.48 (d, 2H), 7.33 (d, 2H), 7.11 (d,2H), 7.05-7.01 (m, 4H), 6.97 (dd, 1H), 6.79 (dd, 1H), 6.50 (brs, 1H),6.36 (dd, 1H), 3.96-3.92 (m, 2H), 3.42-3.34 (m, 2H), 3.04 (s, 3H),2.06-1.95 (m, 2H), 1.79-1.75 (m, 2H), 1.66 (brs, 1H).

Example 14(10):N-{3-(4-fluorophenoxy)-5-[4-(methylsulphonyl)phenoxy]phenyl}-4-hydroxy-4-[4-(trifluoromethyl)phenyl]-1-piperidinecarboxamide

TLC: Rf 0.35 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 7.87 (d, 2H), 7.63 (d, 2H), 7.58 (d, 2H), 7.11 (d,2H), 7.07-7.01 (m, 4H), 6.97 (dd, 1H), 6.79 (dd, 1H), 6.48 (brs, 1H),6.37 (dd, 1H), 3.99-3.95 (m, 2H), 3.45-3.37 (m, 2H), 3.05 (s, 3H),2.11-2.01 (m, 2H), 1.82-1.77 (m, 2H), 1.71 (brs, 1H).

Example 14(11):N-[3-(4-carbamoyl-3-methylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.15 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 7.40 (d, 1H), 7.09-6.95 (m, 4H), 6.86 (d, 1H),6.83-6.77 (m, 2H), 6.73 (t, 1H), 6.54 (s, 1H), 6.32 (t, 1H), 5.95 (br.s., 1H), 5.60 (br. s., 1H), 3.83-3.70 (m, 2H), 3.33-3.09 (m, 2H), 2.46(s, 3H) 1.64-1.45 (m, 4H), 1.43-1.26 (m, 7H), 1.12 (s, 1H), 0.84 (t,6H).

Example 14(12):N-[3-(2-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.20 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 8.20 (dd, 1H), 7.48-7.37 (m, 2H), 7.21 (t, 1H),7.08-6.96 (m, 4H), 6.93 (d, 1H), 6.87 (t, 1H), 6.79 (t, 1H), 6.41 (s,1H), 6.33 (t, 1H), 5.73 (br. s., 1H), 3.83-3.72 (m, 2H), 3.34-3.15 (m,2H), 1.66-1.50 (m, 4H), 1.44-1.29 (m, 7H), 1.06 (s, 1H), 0.85 (t, 6H).

Example 14(13):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-hydroxy-4-(3-pentanyl)-1-piperidinecarboxamide

TLC: Rf 0.37 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃+CD₃OD): δ 7.74 (m, 2H), 7.10-6.84 (m, 6H), 6.84 (m, 1H),6.79 (m, 1H), 6.69 (m, 1H), 6.33 (t, 1H), 3.81 (m, 2H), 3.19 (m, 2H),1.80-1.40 (m, 5H), 1.20-1.08 (m, 4H), 0.94 (t, 6H).

Example 14(14):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-hydroxy-4-phenyl-1-piperidinecarboxamide

TLC: Rf 0.35 (dichloromethane:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 8.61 (s, 1H), 7.90 (d, 3H), 7.45 (d, 2H), 7.32-7.05(m, 11H), 7.00 (dd, 1H), 6.27 (dd, 1H), 5.05 (s, 1H), 3.97-3.93 (m, 2H),3.19-3.11 (m, 2H), 1.85-1.78 (m, 2H), 1.60-1.55 (m, 2H).

Example 14(15):N-[3-(4-fluorophenoxy)-5-(4-sulphamoylphenoxy)phenyl]-4-(4-fluorophenyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 7.87 (d, 2H), 7.44 (d, 2H), 7.41 (d, 2H), 7.09-7.01(m, 6H), 6.94 (dd, 1H), 6.77 (dd, 1H), 6.45 (brs, 1H), 6.36 (dd, 1H),4.77 (brs, 2H), 3.95-3.92 (m, 2H), 3.44-3.35 (m, 2H), 2.07-1.97 (m, 2H),1.82-1.78 (m, 2H).

Example 14(16):N-{3-(4-fluorophenoxy)-5-[4-(methylsulphonyl)phenoxy]phenyl}-4-(4-fluorophenyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.38 (hexane:ethyl acetate=1:2);

¹H-NMR (CDCl₃): δ 7.87 (d, 2H), 7.43 (dd, 2H), 7.12 (d, 2H), 7.09-7.01(m, 6H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.45 (brs, 1H), 6.36 (dd, 1H),3.97-3.92 (m, 2H), 3.45-3.36 (m, 2H), 3.05 (s, 3H), 2.08-1.98 (m, 2H),1.83-1.79 (m, 2H).

Example 14(17):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(3-fluorophenyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.53 (ethyl acetate);

¹H-NMR (CDCl₃): δ 7.87-7.71 (m, 2H), 7.40-7.30 (m, 1H), 7.23-7.13 (m,2H), 7.09-6.91 (m, 7H), 6.86 (t, 1H), 6.81 (t, 1H), 6.42 (s, 1H) 6.36(t, 1H) 6.20-5.40 (m, 2H), 4.02-3.91 (m, 2H), 3.47-3.33 (m, 2H)2.12-1.92 (m, 2H) 1.85-1.75 (m, 2H), 1.60 (s, 1H).

Example 14(18):N-[3-(4-carbamoyl-2-chlorophenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.67 (chloroform:methanol=9:1);

¹H-NMR (CD₃OD): δ 8.02 (d, 1H), 7.79 (m, 1H), 7.18-7.00 (m, 5H), 6.85(m, 2H), 6.23 (t, 1H), 3.82 (m, 2H), 3.20 (m, 2H), 1.64-1.42 (m, 11H),0.86 (t, 6H).

Example 14(19):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(3,3-dimethyl-1-butyn-1-yl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.49 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.76 (d, 2H), 6.93-7.12 (m, 6H), 6.81-6.85 (m, 1H),6.78 (t, 1H), 6.44 (br. s., 1H), 6.35 (t, 1H), 5.77 (br. s, 2H),3.63-3.84 (m, 2H), 3.27 (ddd, 2H), 2.01 (s, 1H), 1.63-1.94 (m, 4H), 1.21(s, 9H).

Example 14(20):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-hydroxy-4-isopropyl-1-piperidinecarboxamide

TLC: Rf 0.39 (dichloromethane:methanol=10:1);

¹H-NMR (DMSO-d₆): δ 8.54 (s, 1H), 7.92 (brs, 1H), 7.89 (d, 2H), 7.30(brs, 1H), 7.23 (t, 2H), 7.13-7.04 (m, 4H), 7.02 (dd, 1H), 6.98 (dd,1H), 6.26 (dd, 1H), 4.00 (s, 1H), 3.84-3.80 (m, 2H), 3.04-2.95 (m, 2H),1.49-1.27 (m, 5H), 0.81 (d, 6H).

Example 14(21):N-[3-(4-carbamoyl-3-chlorophenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.54 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.74 (m, 2H), 7.10-6.80 (m, 8H), 6.58-6.30 (m, 3H),5.78 (m, 1H), 3.76 (m, 2H), 3.28 (m, 2H), 1.70-1.20 (m, 11H), 1.04 (s,1H), 0.85 (t, 6H).

Example 14(22):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-cycloheptyl-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.27 (ethyl acetate);

¹H-NMR (CDCl₃): δ 7.77 (d, 2H), 6.96-7.09 (m, 6H), 6.85 (t, 1H), 6.79(t, 1H), 6.44 (s, 1H), 6.34 (t, 1H) 6.04 (br. s., 1H), 5.52 (br. s.,1H), 3.73-3.87 (m, 2H), 3.22 (td, 2H) 1.16-1.88 (m, 17H), 1.07 (s, 1H).

Example 14(23):N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethyl-1-buten-1-yl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.48 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.75 (d, 2H), 6.93-7.18 (m, 6H), 6.70-6.93 (m, 2H),6.55 (s, 1H), 6.33 (s, 1H), 5.77 (br. d, 2H), 5.17 (s, 1H), 3.62 (d, 2H)3.18-3.52 (m, 2H), 2.36 (q, 2H), 2.01 (q, 2H), 1.46-1.88 (m, 4H),1.31-1.46 (m, 1H), 0.99 (q, 6H).

Example 14(24):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(methylsulphamoyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.38 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 7.83-7.71 (m, 2H), 7.12-6.96 (m, 6H), 6.93 (t, 1H),6.78 (t, 1H), 6.47 (s, 1H), 6.34 (t, 1H), 4.36 (q, 1H), 3.85-3.65 (m,2H), 3.38-3.09 (m, 2H), 2.66 (d, 3H), 1.69-1.49 (m, 4H), 1.42-1.29 (m,7H), 1.08 (s, 1H), 0.85 (t, 6H).

Example 14(25):N-{3-[4-(dimethylsulphamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.46 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 7.77-7.66 (m, 2H), 7.12-6.98 (m, 6H), 6.95 (t, 1H),6.79 (t, 1H), 6.41 (s, 1H), 6.34 (t, 1H), 3.85-3.70 (m, 2H), 3.36-3.19(m, 2H), 2.70 (s, 6H), 1.68-1.50 (m, 4H), 1.44-1.28 (m, 7H), 1.04 (s,1H), 0.85 (t, 6H).

Example 14(26):4-(2-ethylbutyl)-N-{3-[2-fluoro-4-(methylsulphonyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.60 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.74 (m, 1H), 7.66 (m, 1H), 7.14 (t, 1H), 7.10-6.98(m, 5H), 6.76 (t, 1H), 6.47 (m, 1H), 6.34 (t, 1H), 3.78 (m, 2H), 3.28(m, 2H), 3.07 (s, 3H), 1.66-1.20 (m, 11H), 1.07 (s, 1H), 0.85 (t, 6H).

Example 14(27):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[3-hydroxy-4-(methylsulphonyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.39 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.58 (d, 1H), 6.89-7.07 (m, 5H), 6.82 (br. s., 1H),6.39-6.63 (m, 3H), 6.30 (br. s., 1H), 3.78 (d, 2H), 3.18-3.36 (m, 2H),3.03 (br. s., 3H), 1.55-1.63 (m, 4H), 1.30-1.42 (m, 6H), 0.85 (t, 6H).

Example 14(28):N-[3-(4-carbamoyl-3-hydroxyphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.16 (hexane:ethyl acetate=2:3);

¹H-NMR (CDCl₃): δ 7.30 (d, 1H), 7.15 (dd, 1H), 6.93-7.08 (m, 5H),6.80-6.83 (m, 1H), 6.49 (t, 1H), 6.42 (s, 1H), 6.26-6.31 (m, 1H),3.71-3.80 (m, 2H), 3.18-3.33 (m, 2H), 1.54-1.61 (m, 4H), 1.29-1.43 (m,7H), 0.85 (t, 6H).

Example 14(29):4-(2-ethylbutyl)-N-{3-[4-(ethylsulphonyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.29 (hexane:ethyl acetate=2:3);

¹H-NMR (CDCl₃): δ 7.83 (dd, 2H), 7.10 (dd, 2H), 7.01-7.05 (m, 4H),6.95-6.97 (m, 1H), 6.76-6.79 (m, 1H), 6.37 (s, 1H), 6.33-6.36 (m, 1H),3.77 (dt, 2H), 3.21-3.34 (m, 2H), 3.10 (q, 2H), 1.57-1.65 (m, 4H),1.32-1.44 (m, 7H), 1.24-1.32 (m, 3H), 1.02 (s, 1H), 0.85 (t, 6H).

Example 14(30):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(methylcarbamoyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.20 (hexane:ethyl acetate=3:7);

¹H-NMR (CDCl₃): δ 7.83-7.58 (m, 2H), 7.10-6.93 (m, 6H), 6.80 (d, 2H),6.37 (s, 1H), 6.33 (t, 1H), 6.07 (br. s., 1H), 3.85-3.70 (m, 2H),3.39-3.14 (m, 2H), 3.00 (d, 3H), 1.62-1.55 (m, 4H), 1.44-1.28 (m, 7H),1.03 (s, 1H), 0.86 (t, 6H).

Example 15:4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(tetrahydro-2H-pyran-2-yloxy)carbamoyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide

The compound prepared in Example 9(1) (20 mg) was dissolved in DMF (200μL), added with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (4.2 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (19mg) and 1-hydroxybenzotriazole monohydrate (HOBt) (15 mg) and stirred atroom temperature for 24 hours. The reaction solution was diluted withethyl acetate and added with water and the aqueous layer was extractedwith MTBE. The organic layer was combined, washed with water, asaturated sodium hydrogen carbonate aqueous solution and a saturatedammonium chloride aqueous solution and then concentrated. The resultingresidue was purified by silica gel column chromatography(dichloromethane:methanol=20:1) to give the titled compound (19.6 mg)having the following physical properties.

TLC: Rf 0.42 (dichloromethane:methanol=10:1).

Examples 15(1) to 15(7)

The compounds of the following Examples were obtained by carrying outthe process with the same purpose as Example 15 using the compoundprepared in Example 9(1) and a corresponding amine derivative in theplace of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine.

Example 15(1): 4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.39 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.77-7.64 (m, 2H), 7.08-6.94 (m, 6H), 6.83-6.75 (m,2H), 6.42 (s, 1H), 6.33 (t, 1H), 6.13-5.96 (m, 1H), 3.83-3.72 (m, 2H),3.55-3.44 (m, 2H), 3.34-3.16 (m, 2H), 1.64-1.50 (m, 4H), 1.43-1.29 (m,7H) 1.25 (t, 3H), 1.04 (s, 1H) 0.85 (t, 6H).

Example 15(2):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(isopropylcarbamoyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.42 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.71 (d, 2H), 7.07-6.97 (m, 6H), 6.83-6.78 (m, 2H),6.37 (d, 1H), 6.32 (t, 1H), 5.92-5.78 (m, 1H), 4.36-4.14 (m, 1H),3.83-3.72 (m, 2H), 3.38-3.13 (m, 2H), 1.66-1.49 (m, 4H), 1.45-1.30 (m,7H), 1.26 (d, 6H), 1.03 (s, 1H), 0.85 (t, 6H).

Example 15(3):4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(4-morpholinylcarbonyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.42 (dichloromethane:methanol=1:2);

¹H-NMR (CDCl₃): δ 7.45-7.34 (m, 2H), 7.08-6.97 (m, 6H), 6.83 (t, 1H),6.74 (t, 1H), 6.39 (s, 1H), 6.33 (t, 1H) 3.89-3.49 (m, 10H), 3.34-3.17(m, 2H), 1.62-1.52 (m, 4H), 1.45-1.27 (m, 7H), 1.05 (s, 1H), 0.85 (t,6H).

Example 15(4):4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(3-hydroxy-1-azetidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.25 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.58-7.49 (m, 2H), 7.08-6.95 (m, 6H), 6.89 (t, 1H),6.83 (d, 1H), 6.74 (t, 1H), 6.32 (t, 1H), 4.78-4.52 (m, 1H), 4.39 (br.s., 2H), 4.24-3.83 (m, 2H), 3.85-3.70 (m, 2H), 3.34-3.01 (m, 2H), 1.61(s, 1H), 1.60-1.52 (m, 4H), 1.45-1.27 (m, 7H), 1.24 (d, 1H), 0.83 (t,6H).

Example 15(5):4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(3-hydroxy-1-pyrrolidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.23 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.55-7.40 (m, 2H), 7.10-7.00 (m, 6H), 6.99-6.92 (m,1H), 6.90-6.79 (m, 1H), 6.65 (t, 1H), 6.32 (t, 1H), 4.65-4.35 (m, 1H),3.90-3.68 (m, 4H), 3.67-3.34 (m, 2H), 3.30-3.05 (m, 2H), 2.28-2.18 (m,1H), 2.15-1.92 (m, 2H), 1.64-1.51 (m, 4H), 1.42-1.25 (m, 7H), 1.16 (br.s., 1H) 0.84 (t, 6H).

Example 15(6):4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.30 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.39-7.31 (m, 2H), 7.06-6.96 (m, 6H), 6.93 (t, 1H),6.79-6.70 (m, 1H), 6.65 (t, 1H), 6.32 (t, 1H), 4.40-3.90 (m, 3H),3.85-3.70 (m, 2H), 3.41-3.07 (m, 4H), 2.10-1.80 (m, 2H), 1.80-1.70 (m,1H), 1.66-1.45 (m, 6H), 1.43-1.24 (m, 7H), 1.17 (br. s., 1H), 0.84 (t,6H).

Example 15(7):4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(3-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide

TLC: Rf 0.35 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.36 (d, 2H), 7.06-6.94 (m, 6H), 6.93-6.72 (m, 3H),6.64 (s, 1H), 6.32 (t, 1H), 4.05-3.50 (m, 4H), 3.49-3.10 (m, 5H),2.45-2.25 (m, 1H), 2.00-1.75 (m, 2H), 1.70-1.40 (m, 6H), 1.40-1.20 (m,7H), 1.20 (d, 1H), 0.84 (t, 6H).

Example 16:4-(2-ethylbutyl)-N-{3-(4-fluorophenoxy)-5-[4-(hydroxycarbamoyl)phenoxy]phenyl}-4-hydroxy-1-piperidinecarboxamide

The compound prepared in Example 15 (19 mg) was dissolved in ethylacetate (0.5 mL), added with a hydrochloric acid/ethyl acetate solution(4 mol/L, 0.1 mL) and stirred at room temperature for 20 minutes. Thereaction solution was concentrated before purification on preparativeTLC (dichloromethane:methanol=10:1) to give the titled compound (5.1 mg)having the following physical properties.

TLC: Rf 0.23 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.75 (d, 2H), 7.15-6.99 (m, 6H), 6.91 (t, 1H), 6.87(t, 1H), 6.27 (t, 1H), 3.88-3.70 (m, 2H), 3.28-3.14 (m, 2H), 1.68-1.48(m, 4H), 1.44-1.26 (m, 7H), 0.87 (t, 6H).

Example 17:2-methyl-2-propanyl-3-hydroxy-3-isobutyl-1-azetidinecarboxylate

Under an argon atmosphere, to a 100-mL three-neck flask was added a 0.6M lanthanum chloride/2 lithium chloride (LaCl₃/2LiCl) solution in THF(31.0 mL) which was added with a 2.0 M isobutylmagnesium chloridesolution in THF (6.9 mL) while cooling to 0° C. The mixture was stirredat 0° C. for 3 hours before addition of2-methyl-2-propanyl-3-oxo-1-azetidinecarboxylate (1.6 g) dissolved inTHF (4.0 mL) at 0° C. The reaction solution was stirred from 0° C. toroom temperature over 15 hours before addition of a 5% acetic acidaqueous solution (30 mL) and extraction twice with ethyl acetate. Theorganic layer was washed with a saturated sodium chloride solution anddried over anhydrous sodium sulphate and the solvent was distilled offto give a brown oily substance (3.2 g). The substance was purified bycolumn chromatography (medium pressure preparative liquid chromatographyW-prep 2XY from Yamazen Corporation (column: main column 2L, injectioncolumn L; hexane:ethyl acetate 9:1→7:3)) to give the titled compound(2.0 g) having the following physical properties.

TLC: Rf 0.53 (hexane:ethyl acetate=2:1).

Example 18: 3-isobutyl-3-azetidinol

To a 200-mL pear-shaped evaporating flask were added the compoundprepared in Example 17 (2.0 g) and methanol (9 mL) and then a 4 Nhydrochloric acid/ethyl acetate solution (11 mL) at 0° C. The mixturewas stirred at room temperature for 7 hours, again cooled to 0° C.,added with a 5 N sodium hydroxide aqueous solution (43.5 mL) andextracted twice with methylene chloride. The organic layer was driedover anhydrous sodium sulphate and the solvent was distilled off underreduced pressure to give the titled compound (973.5 mg) having thefollowing physical properties. The resulting titled compound wasdirectly used for the next reaction without purification.

TLC: Rf 0.69 (ethyl acetate:methanol=3:1).

Example 19:2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isobutyl-1-azetidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

The titled compound (41 mg) having the following physical properties wasobtained by carrying out the processes with the same purposes as Example8→Example 9 using the compound prepared in Example 18 (64.6 mg) and thecompound prepared in Example 7 (342.5 mg).

TLC: Rf 0.15 (dichloromethane:ethanol=20:1);

¹H-NMR (CDCl₃): δ 7.31 (d, 2H), 6.87-7.11 (m, 6H), 6.76 (s, 1H), 6.66(s, 1H), 6.21-6.37 (m, 2H), 3.70-4.01 (m, 4H), 2.55 (br. s., 2H),1.72-1.97 (m, 1H), 1.61 (d, 2H), 1.56 (s, 6H), 0.91 (d, 6H).

Examples 19(1) to 19(9)

The compounds of the following Examples were obtained by carrying outthe process with the same purpose as Example 19 using a correspondingcyclic amine derivative in the place of the compound prepared in Example18 and the compound prepared in Example 7.

Example 19(1):2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isobutyl-1-pyrrolidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.13 (dichloromethane:ethanol=20:1);

¹H-NMR (CDCl₃): δ 7.29-7.39 (m, 2H), 6.89-7.07 (m, 6H), 6.84 (t, 1H),6.71 (t, 1H), 6.30 (t, 1H), 6.20 (s, 1H), 3.39-3.66 (m, 3H), 3.26 (d,1H), 2.52 (br. s., 2H), 1.73-2.06 (m, 3H), 1.44-1.68 (m, 8H), 0.97 (dd,6H).

Example 19(2):2-{4-[3-({[(3R,4S)-3-fluoro-4-hydroxy-4-isobutyl-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.31 (dichloromethane:ethanol=20:1);

¹H-NMR (CDCl₃): δ 7.29-7.43 (m, 2H), 6.90-7.10 (m, 6H), 6.77 (t, 1H),6.65 (t, 1H), 6.43 (s, 1H), 6.31 (t, 1H), 4.20-4.48 (m, 1H), 3.94 (ddd,1H), 3.54 (d, 1H), 3.19-3.42 (m, 2H), 1.99-2.25 (m, 2H), 1.73-1.97 (m,2H), 1.34-1.69 (m, 9H), 0.98 (dd, 6H).

Example 19(3):2-{4-[3-(4-fluorophenoxy)-5-{[(3-hydroxy-3-isopropyl-1-pyrrolidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic Acid

TLC: Rf 0.45 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.42-7.34 (m, 2H), 7.14-6.94 (m, 6H), 6.93-6.90 (m,1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.57 (dd, 2H), 3.48-3.32 (m, 2H),2.04-1.68 (m, 3H), 1.55 (s, 6H), 0.98 (d, 6H).

Example 19(4):2-{4-[3-{[(3-cyclopentyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.47 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.41-7.34 (m, 2H), 7.15-6.95 (m, 6H), 6.94-6.91 (m,1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.61-3.50 (m, 2H), 3.45-3.32 (m, 2H),2.15-1.97 (m, 1H), 1.89 (t, 2H), 1.55 (s, 6H), 1.78-1.40 (m, 8H).

Example 19(5):2-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

TLC: Rf 0.48 (dichloromethane:methanol=10:1);

¹H-NMR (CD₃OD): δ 7.41-7.35 (m, 2H), 7.13-6.94 (m, 6H), 6.93-6.90 (m,1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.60-3.50 (m, 2H), 3.47-3.32 (m, 2H),1.98-1.61 (m, 7H), 1.55 (s, 6H), 1.49-1.09 (m, 6H).

Example 19(6):1-{4-[3-{[(3-cyclopentyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.49 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.32-7.26 (m, 2H), 7.07-6.97 (m, 4H), 6.96-6.91 (m,2H), 6.90 (t, 1H), 6.70 (t, 1H), 6.32 (t, 1H), 6.20 (s, 1H), 3.64-3.47(m, 2H), 3.43 (d, 1H), 3.30 (d, 1H), 2.04-1.95 (m, 1H), 1.93-1.84 (m,2H), 1.77-1.49 (m, 8H), 1.46-1.33 (m, 2H), 1.27-1.19 (m, 2H).

Example 19(7):1-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxylicAcid

TLC: Rf 0.49 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.31-7.26 (m, 2H), 7.06-6.97 (m, 4H), 6.96-6.91 (m,2H), 6.90 (t, 1H), 6.70 (t, 1H), 6.32 (t, 1H), 6.21 (s, 1H), 3.64-3.50(m, 2H), 3.46 (d, 1H), 3.27 (d, 1H), 1.99-1.55 (m, 9H), 1.47-1.31 (m,2H), 1.30-1.07 (m, 6H).

Example 19(8):2-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenoxy}-2-methylpropanoicAcid

TLC: Rf 0.28 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.05-6.94 (m, 4H), 6.92-6.86 (m, 4H), 6.75 (t, 1H),6.60 (t, 1H), 6.30-6.25 (m, 2H), 3.57-3.47 (m, 2H), 3.43 (d, 1H), 3.25(d, 1H), 1.96-1.85 (m, 1H), 1.85-1.66 (m, 6H), 1.58 (s, 6H), 1.45-1.33(m, 1H), 1.24-1.11 (m, 5H).

Example 19(9):1-{4-[3-{[(3-cyclohexyl-3-hydroxy-1-pyrrolidinyl)carbonyl]amino}-5-(4-fluorophenoxy)phenoxy]phenoxy}cyclopropanecarboxylicAcid

TLC: Rf 0.28 (dichloromethane:methanol=10:1);

¹H-NMR (CDCl₃): δ 7.06-6.92 (m, 4H), 6.89-6.78 (m, 4H), 6.63-6.51 (m,3H), 6.29 (t, 1H), 3.50-3.29 (m, 3H), 3.15 (d, 1H), 1.89-1.59 (m, 6H),1.58-1.48 (m, 3H), 1.35-1.03 (m, 8H).

Example 20: Methyl 4-{[3-(4-fluorophenoxy)-5-nitrophenyl]thio}benzoate

Under an argon atmosphere, the compound prepared in Example 10 (6.01 g)was dissolved in DMA (60 mL), potassium carbonate (7.62 g) and4-carbomethoxybenzene thiol (2.80 g) were added thereto and the reactionmixture was stirred at 75° C. for 3 hours. The reaction mixture wascooled to room temperature, poured to water, extracted with MTBE,sequentially washed with water and a saturated sodium chloride solution,dried over anhydrous sodium sulphate and concentrated under reducedpressure. The concentrate was purified by silica gel columnchromatography (hexane:ethyl acetate=9:1→4:1) to give the titledcompound (2.28 g) having the following physical properties.

TLC: Rf 0.59 (hexane:ethyl acetate=4:1).

Example 21: Methyl 4-{[3-amino-5-(4-fluorophenoxy)phenyl]thio}benzoate

The compound prepared in Example 20 (1.12 g) and acetic acid (11.2 mL)were dissolved in water (0.86 mL), added with iron (777 mg) with smallportions and the reaction was allowed to proceed at 90° C. for 1.5hours. The reaction solution was cooled to room temperature, added withethyl acetate (30 mL) and stirred for 20 minutes. Celite (trade name)was used for filtration and the filtrate was concentrated under reducedpressure after addition of toluene. The resulting residue was added withethyl acetate, washed with water, a saturated sodium hydrogen carbonatesolution and a saturated sodium chloride solution, dried over anhydroussodium sulphate and concentrated. The resulting residue was purified bysilica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to givethe titled compound (830 mg) having the following physical properties.

TLC: Rf 0.17 (hexane:ethyl acetate=4:1).

Example 22:4-{[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)phenyl]thio}benzoicacid

The titled compound (12.0 g) having the following physical propertieswas obtained by carrying out the processes with the same purposes asExample 7→Example 8→Example 9 using the compound prepared in Example 21;2,2,2-trichloroethyl chloroformate; and 4-(4-fluorophenyl)-4-piperidinolin the place of 4-isobutyl-4-piperidinol.

TLC: Rf 0.52 (chloroform:methanol:ethanol=9:1:0.1);

¹H-NMR (CD₃OD): δ 1.73, 2.00, 3.32-3.44, 4.03, 6.62, 6.95-7.18,7.24-7.36, 7.46-7.55, 7.86-7.99.

Example 23: tert-butyl4-hydroxy-4-isobutyl-2-methylpiperidine-1-carboxylate

Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask wasweighed a solution of lanthanum chloride lithium chloride complex in THF(15.6 mL) and cooled to 0° C. To the solution was added dropwise asolution of isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0°C. for 3 hours. A solution of tert-butyl2-methyl-4-oxopiperidine-1-carboxylate (1 g) in THF (2.0 mL) was furtheradded dropwise. The reaction solution was stirred at 0° C. for 1 hour,heated to 25° C., poured to hydrochloric acid and extracted with ethylacetate. The organic layer was washed with water and a saturated sodiumchloride solution and dried over anhydrous magnesium sulphate. Thefiltrate was concentrated and the resulting residue was purified bysilica gel chromatography (hexane:ethyl acetate=9:1→3:1) to give thetitled compound (450 mg) having the following physical properties.

TLC: Rf 0.51 (hexane:ethyl acetate=3:1).

Example 24: 2-methyl-4-isobutyl-4-hydroxypiperidine Hydrochloride

In a 100-mL pear-shaped evaporating flask was weighed the compoundprepared in Example 23 (440 mg) and added a solution of hydrogenchloride (4 mol/L) in 1,4-dioxane (5.0 mL). The reaction solution wasstirred at 25° C. for 30 minutes before concentration to give the titledcompound (336 mg) having the following physical properties.

¹H-NMR (CD₃OD): δ 1.01 (d, 6H), 1.34 (d, 3H), 1.50-1.58 (m, 3H),1.67-1.88 (m, 2H), 1.92-2.02 (m, 2H), 3.03 (dt, 1H), 3.27-3.38 (m, 2H).

Example 25:2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-2-methyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid

The titled compound (60 mg) having the following physical properties wasobtained by carrying out the processes with the same purposes as Example8→Example 9 using the compound prepared in Example 24 (48 mg) and thecompound prepared in Example 7 (100 mg).

TLC: Rf 0.33 (chloroform:methanol=19:1);

¹H-NMR (CDCl₃): δ 0.97 (dd, 6H), 1.36 (t, 2H), 1.38 (d, 3H), 1.47-1.75(m, 10H), 1.77-1.89 (m, 1H), 3.36 (dt, 1H), 3.71-3.79 (m, 1H), 4.26-4.35(m, 1H), 6.29 (t, 1H), 6.38 (s, 1H), 6.69 (t, 1H), 6.81 (t, 1H),6.96-7.02 (m, 6H), 7.35 (d, 2H).

Example 26: Ethyl2-(benzhydrylideneamino)-2-[4-{3-(4-fluorophenoxy)-5-nitrophenoxy}phenyl]acetate

To the compound prepared in Example 11 (1.0 g) were addedethyl[(diphenylmethylene)amino]acetate (652 mg) and potassium phosphate(1.41 g) and suspended in toluene (7.4 mL). The reaction system wasdegassed, purged with argon, added with Pd(t-Bu₃P)₂ (23 mg), degassedagain and purged with argon. The reaction solution was stirred at 100°C. for 17 hours, cooled to 0° C., adjusted to pH 7 by addition of waterand 1 N hydrochloric acid and extracted with ethyl acetate. The organiclayer was sequentially washed with water and a saturated sodium chloridesolution and dried over anhydrous magnesium sulphate. The resultingresidue obtained after concentration was purified by silica gelchromatography (hexane:ethyl acetate=100:0→9:1) to give the titledcompound (456 mg) having the following physical properties.

TLC: Rf 0.36 (hexane:ethyl acetate=3:1).

Example 27: Ethylamino{4-[3-(4-fluorophenoxy)-5-nitrophenoxy]phenyl}acetate

The compound prepared in Example 26 (356 mg) was dissolved in ethanol (4mL) and DME (3 mL), added with 1 N hydrochloric acid (1.8 mL) andstirred at room temperature for 15 hours. The concentrated reactionsolution was cooled to 0° C., neutralized with saturated aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic layer wassequentially washed with water and a saturated sodium chloride solutionand dried over anhydrous magnesium sulphate. The resulting residueobtained after concentration was purified by silica gel chromatography(hexane:ethyl acetate=80:20→60:40) to obtain the titled compound (253mg) having the following physical properties.

TLC: Rf 0.28 (hexane:ethyl acetate=1:1).

Example 28: Ethyl2-(benzyloxycarbonylamino)-2-{4-[3-(4-fluorophenoxy)-5-nitrophenoxy]phenyl}acetate

The compound prepared in Example 27 (253 mg) was dissolved in ethylacetate (2.5 mL) and added with sodium hydrogen carbonate (100 mg) andbenzyl chloroformate (112 mg) at 0° C. The reaction solution was stirredat room temperature for 13 hours, added with water and extracted withethyl acetate. The organic layer was sequentially washed with water anda saturated sodium chloride solution and dried over anhydrous magnesiumsulphate. The resulting residue obtained after concentration waspurified by silica gel chromatography (hexane:ethyl acetate=100:0→85:15)to give the titled compound (234 mg) having the following physicalproperties.

TLC: Rf 0.32 (hexane:ethyl acetate=5:1).

Example 29: Ethyl2-{4-[3-amino-5-(4-fluorophenoxy)phenoxy]phenyl}-2-(benzyloxycarbonylamino)acetate

To the compound prepared in Example 28 (253 mg) were added iron (166mg), zinc (194 mg), ammonium chloride (32 mg), water (0.2 mL) andethanol (1.5 mL) and stirred at 70° C. for 3 hours. The reactionsolution was cooled to room temperature, diluted with water and ethylacetate and filtered with celite. The resulting filtrate was added withsaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was sequentially washed with water and a saturatedsodium chloride solution and dried over anhydrous magnesium sulphate togive the titled compound (278 mg) having the following physicalproperties.

TLC: Rf 0.17 (hexane:ethyl acetate=3:1).

Example 30:Amino{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}aceticAcid

The titled compound (28.4 mg) having the following physical propertieswas obtained by carrying out the processes with the same purposes asExample 7→Example 8→Example 9→Example 6 using the compound prepared inExample 29 and 4-isobutyl-4-piperidinol.

TLC: Rf 0.15 (dichloromethane:methanol:aqueous ammonia=160:30:1);

¹H-NMR (CD₃OD): δ 7.45 (d, 2H), 7.13-6.97 (m, 6H), 6.83 (dt, 2H), 6.20(t, 1H), 4.50 (s, 1H), 3.80 (d, 2H), 3.29-3.16 (m, 2H), 1.92-1.80 (m,1H), 1.67-1.45 (m, 4H), 1.39 (d, 2H), 0.97 (d, 6H).

Example 31: Benzyl 3-(diethylcarbamoyl)-1-pyrrolidinecarboxylate

Under an argon atmosphere,1-[(benzyloxy)carbonyl]-3-pyrrolidinecarboxylic acid (500 mg) wasdissolved in DMF (5 mL), added with N,N-diethylamine (0.293 g), furtherwith EDC (769 mg) and HOBt (542 mg) and stirred at room temperature for72 hours. The reaction solution was diluted with ethyl acetate,sequentially washed with 1 N hydrochloric acid, a 1 N sodium hydroxideaqueous solution, water and a saturated sodium chloride solution anddried over anhydrous magnesium sulphate before distillation of thesolvent. The resulting residue was purified by silica gel chromatography(hexane:ethyl acetate=95:5→0:1) to give the titled compound (556 mg)having the following physical properties.

¹H-NMR (CDCl₃): δ 7.38-7.25 (m, 5H), 5.13 (s, 2H), 3.75-3.04 (m, 8H),2.20 (m, 2H), 1.20 (t, 3H), 1.11 (t, 3H).

Example 32: N,N-diethyl-3-pyrrolidinecarboxamide

The compound prepared in Example 31 (556 mg) was dissolved in ethanol(10 mL) and ethyl acetate (20 mL) and added with 5% palladium carbon(100 mg) and the reaction solution was stirred under a hydrogenatmosphere at room temperature for 8 hours. The reaction solution wasfiltered with celite and the solvent was distilled off to give thetitled compound having the following physical properties. The resultingtitled compound was used for the next reaction without furtherpurification.

¹H-NMR (CDCl₃): δ 3.50-2.74 (m, 8H), 1.97 (m, 2H), 1.20 (t, 3H), 1.11(t, 3H).

Example 33:2-{4-[3-({[3-(diethylcarbamoyl)-1-pyrrolidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid

The titled compound (59.4 g) having the following physical propertieswas obtained by carrying out the processes with the same purposes asExample 8→Example 9 using the compound prepared in Example 32 (29.8 mg)and the compound prepared in Example 7 (100 mg).

TLC: Rf 0.60 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.31 (m, 2H), 7.98-6.88 (m, 7H), 6.68 (m, 1H), 6.44(m, 1H), 6.30 (m, 1H), 3.74-3.12 (m, 8H), 2.25-2.00 (m, 2H), 1.55 (s,6H), 1.19 (t, 3H), 1.09 (t, 3H).

Example 33(1):2-{4-[3-(4-fluorophenoxy)-5-({[3-(isopropylcarbamoyl)-1-pyrrolidinyl]carbonyl}amino)phenoxy]phenyl}-2-methylpropanoicAcid

The titled compound (63.6 mg) having the following physical propertieswas obtained by carrying out the process with the same purpose asExample 33 using the compound prepared in Example 7 (100 mg) and acorresponding pyrrolidine derivative (27.4 mg) in the place of thecompound prepared in Example 32.

TLC: Rf 0.54 (chloroform:methanol=9:1);

¹H-NMR (CDCl₃): δ 7.31 (m, 2H), 7.04-6.80 (m, 7H), 6.68 (m, 1H), 6.48(m, 1H), 6.30 (m, 1H), 5.64 (d, 1H), 4.03 (m, 1H), 3.62-3.50 (m, 3H),3.33 (m, 1H), 2.79 (m, 1H), 2.09 (m, 2H), 1.56 (s, 6H), 1.11 (m, 6H).

Example 34: Methyl 3,5-dinitrobenzoate

In methanol (100 mL) was dissolved 3,5-dinitrobenzoyl chloride anddiisopropylethylamine (4.53 mL) was added thereto while cooling withice. The reaction solution was stirred for 1 hour and then the solventwas distilled off. The resulting substance was diluted with ethylacetate, sequentially washed with water and a saturated sodium chloridesolution and dried over anhydrous magnesium sulphate before distillationof the solvent to give the titled compound (4.73 g) having the followingphysical properties.

TLC: Rf 0.31 (hexane:ethyl acetate=5:1).

Example 35: Methyl 3-(4-fluorophenoxy)-5-nitrobenzoate

The compound prepared in Example 34 (4.73 g) was dissolved in DMF (40mL), added with 4-fluorophenol (2.34 g) and potassium phosphate (5.32 g)and stirred overnight at 80° C. The reaction solution was diluted withethyl acetate, sequentially washed with water and a saturated sodiumchloride solution and dried over anhydrous magnesium sulphate beforedistillation of the solvent. The resulting residue was purified bysilica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give thetitled compound (4.81 g) having the following physical properties.

TLC: Rf 0.47 (hexane:ethyl acetate=5:1).

Example 36: Methyl3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoate

The titled compound (495 mg) having the following physical propertieswas obtained by carrying out the processes with the same purposes asExample 6→Example 7→Example 8 using the compound prepared in Example 35and 4-isobutyl-4-piperidinol.

¹H-NMR (CDCl₃): δ 7.40-7.20 (m, 7H), 5.13 (s, 2H), 3.94 (m, 2H), 3.22(m, 2H), 2.46 (m, 1H), 1.83 (m, 2H), 1.57 (m, 6H).

Example 37:3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoicAcid

The compound prepared in Example 36 (495 mg) was dissolved in methanol(5 mL), added with a 2 N sodium hydroxide aqueous solution (1.11 mL) andstirred at 45° C. for 2 hours. The reaction solution was neutralizedwith the equivalent amount of hydrochloric acid before distillation ofthe solvent, dilution with ethanol, filtration and desalting to give thetitled compound (490 mg). The resulting titled compound was used for thenext reaction without further purification.

Example 38:2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoicAcid

Under an argon atmosphere, the compound prepared in Example 37 (75 mg)was dissolved in DMF (1 mL), added with EDC (55.5 mg), HOBt (39.1 mg),diisopropylethylamine (0.05 mL) and benzyl2-(4-hydroxyphenyl)-2-methylpropanoate (56.5 mg) and stirred overnightat room temperature. The reaction solution was diluted with ethylacetate, sequentially washed with water and a saturated sodium chloridesolution and dried over anhydrous magnesium sulphate before distillationof the solvent. The resulting residue was dissolved in methanol (1 mL)and ethyl acetate (1 mL), added with 5% palladium carbon (50 mg) andstirred at room temperature for 2 hours in a hydrogen atmosphere. Thereaction solution was filtered with celite and the solvent was distilledoff. The resulting residue was purified by thin layer chromatography(chloroform:methanol=5:1) to give the titled compound (59.1 mg) havingthe following physical properties.

TLC: Rf 0.62 (chloroform:methanol=5:1);

¹H-NMR (CDCl₃) δ 7.58 (m, 2H), 7.32 (m, 3H), 7.18-6.90 (m, 6H), 3.79 (m,2H), 3.24 (m, 2H), 1.80 (m, 1H), 1.70-1.45 (m, 4H), 1.52 (s, 6H), 1.37(d, 2H), 0.95 (d, 6H).

Example 39:4-cyclopropyl-N-[3-(4-fluorophenoxy)-5-(hydroxymethyl)phenyl]-4-hydroxy-1-piperidinecarboxamide

Under an argon atmosphere, methyl3-{[(4-cyclopropyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)benzoate(201 mg) which was obtained with the same procedure as Example 36 usingthe compound prepared in Example 35 and 4-cyclopropyl-4-piperidinol inthe place of 4-isobutyl-4-piperidinol was dissolved in THF (10 mL),added with diisobutylaluminium hydride (1.407 mL, 1.0 M, a solution intoluene) and stirred at 0° C. for 1.5 hours. The reaction solution wasadded with a sodium sulphate aqueous solution and filtered with celiteand the solvent was distilled off. The reaction solution was furtherdiluted with ethyl acetate, sequentially washed with water and asaturated sodium chloride solution and dried over anhydrous magnesiumsulphate before distillation of the solvent. The resulting residue waspurified by silica gel chromatography (hexane:ethyl acetate=95:5→0:1) togive the titled compound (161 mg) having the following physicalproperties.

¹H-NMR (CDCl₃): δ 7.06 (m, 1H), 7.00-6.88 (m, 5H), 6.79 (m, 1H), 6.58(m, 1H), 4.52 (s, 2H), 3.78 (m, 2H), 3.18 (m, 2H), 1.68-1.44 (m, 4H),0.89 (m, 1H), 0.39-0.32 (m, 4H).

Example 40:2-(4-{[3-{[(4-cyclopropyl-4-hydroxy-1-piperidinyl)carbonyl]amino}-5-(4-fluorophenoxy)benzyl]oxy}phenyl)-2-methylpropanoicAcid

Under an argon atmosphere, the compound prepared in Example 39 (153 mg)was dissolved in THF (12 mL), added with the compound prepared inExample 3 (89.2 mg), diisopropyl azodicarboxylate (0.114 mL) andtriphenylphosphine (110 mg) and stirred overnight at room temperature.The reaction solution was diluted with ethyl acetate, sequentiallywashed with water and a saturated sodium chloride solution and driedover anhydrous magnesium sulphate before distillation of the solvent.The resulting residue was purified by silica gel chromatography(hexane:ethyl acetate=9:1→0:1). The resulting product was furtherdissolved in methanol (2 mL), added with a 2 N sodium hydroxide aqueoussolution (0.575 mL) and stirred at 45° C. for 2 hours. The reactionsolution was neutralized with the equivalent amount of hydrochloric acidbefore concentration and the resulting residue was purified by thinlayer chromatography (chloroform:methanol=5:1) to give the titledcompound (99.0 mg) having the following physical properties.

TLC: Rf 0.58 (chloroform:methanol=5:1);

¹H-NMR (CDCl₃): δ 7.30-6.70 (m, 10H), 6.67 (m, 1H), 6.51 (s, 1H), 4.96(s, 2H), 3.80 (m, 2H), 3.24 (m, 2H), 1.70-1.48 (m, 4H), 1.56 (s, 6H),0.93 (m, 1H), 0.44-0.32 (m, 4H).

Example 41:N-[3-(4-fluorophenoxy)-5-hydroxyphenyl]-4-hydroxy-4-isobutyl-1-piperidinecarboxamide

The titled compound having the following physical properties wasobtained by carrying out the processes with the same purposes as Example4→Example 5→Example 6→Example 7→Example 8 using1,3-difluoro-5-nitrobenzene, phenylmethanol, 4-fluorophenol and4-isobutyl-4-piperidinol.

TLC: Rf 0.52 (hexane:ethyl acetate=1:2).

Example 42: Ethyl{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}(oxo)acetate

The compound prepared in Example 41 (100 mg) and ethyl2-(4-fluorophenyl)-2-oxoacetate (73 mg) were dissolved in DMF (0.7 mL),added with cesium carbonate (79 mg) and stirred at 60° C. After 2 hoursand 4 hours from the initiation of the reaction, ethyl2-(4-fluorophenyl)-2-oxoacetate (73 mg), and ethyl2-(4-fluorophenyl)-2-oxoacetate (73 mg) and cesium carbonate (132 mg)were respectively added and stirring was continued for in total 18hours. The reaction solution was allowed to cool to room temperature,added with water and extracted with ethyl acetate. The organic layer wassequentially washed with water and a saturated sodium chloride solutionand dried over anhydrous magnesium sulphate. The residue obtained afterdistillation under reduced pressure was purified by silica gelchromatography (hexane:ethyl acetate=90:10→50:50) to give the titledcompound (43 mg) having the following physical properties.

TLC: Rf 0.28 (hexane:ethyl acetate=1:1).

Example 43: Ethyl{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}(hydroxy)acetate

The compound prepared in Example 42 (43 mg) was dissolved in methanol (1mL) and stirred at 0° C. The reaction solution was added with sodiumborohydride (3 mg), stirred for 15 minutes, added with water andextracted with ethyl acetate. The organic layer was sequentially washedwith water and a saturated sodium chloride solution and dried overanhydrous magnesium sulphate. The residue obtained after distillationunder reduced pressure was purified by silica gel chromatography(hexane:ethyl acetate=75:25→50:50) to give the titled compound (24 mg)having the following physical properties.

TLC: Rf 0.12 (hexane:ethyl acetate=1:1).

Example 44:{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}(hydroxy)aceticAcid

The compound prepared in Example 43 (24 mg) was dissolved in methanol(0.4 mL), added with a 2 N sodium hydroxide aqueous solution (52 μL) andstirred at 35° C. for 13 hours. The solution was added with 1 Nhydrochloric acid for neutralization at 0° C. and added with water andethyl acetate for extraction. The organic layer was sequentially washedwith water and a saturated sodium chloride solution and dried overanhydrous magnesium sulphate. Distillation under reduced pressure gavethe titled compound (21.6 mg) having the following physical properties.

TLC: Rf 0.16 (dichloromethane:methanol:acetic acid=100:10:1);

¹H-NMR (CDCl₃): δ 7.38 (d, 2H), 7.03-6.90 (m, 6H), 6.78 (s, 1H), 6.64(s, 1H), 6.27 (t, 1H), 5.08 (s, 1H), 3.67 (d, 2H), 3.30-3.18 (m, 2H),1.77 (td, 1H), 1.63-1.46 (m, 4H), 1.34 (d, 2H), 0.92 (d, 6H).

Example 45:N-[3-(4-fluorophenoxy)-5-(4-{2-methyl-1-[(methylsulphonyl)amino]-1-oxo-2-propanyl}phenoxy)phenyl]-4-hydroxy-4-isobutyl-1-piperidinecarboxamide

The compound prepared in Example 9 (320 mg), methanesulphonamide (80mg), EDC (160 mg) and 4-dimethylaminopyridine (104 mg) were suspended indichloromethane (12 mL) and the suspension was heated to 70° C. for 2hours with a microwave. The reaction solution was subjected todistillation under reduced pressure, then dissolved in ethyl acetate andwashed twice with 1 N hydrochloric acid and once with a saturated sodiumchloride solution. The organic layer was subjected to distillation ofthe solvent and the resulting residue was purified by silica gelchromatography (dichloromethane:methanol=16:1). The resulting residuewas further washed with hexane and t-butyl methyl ether to give thetitled compound (215 mg) having the following physical properties.

TLC: Rf 0.45 (dichloromethane:methanol=8:1);

¹H-NMR (CD₃OD): δ 7.32 (d, 2H), 7.16-6.97 (m, 6H), 6.85 (t, 1H), 6.79(t, 1H), 6.21 (t, 1H), 3.88-3.72 (m, 2H), 3.27-3.15 (m, 5H), 1.98-1.76(m, 1H), 1.54 (s, 6H), 1.66-1.47 (m, 4H), 1.39 (d, 2H), 0.97 (d, 6H).

[Method for Preparing Crystals of the Present Compound]

The compounds of Examples in the present invention can be crystallizedaccording to the methods described in Examples or similar methodsthereto.

The crystals were subjected to measurement under the followingconditions and the physical properties described in Examples wereobtained.

[1] X-Ray Powder Diffraction Spectrum <Measurement Conditions>

Instrument: BRUKER D8 DISCOVER with GADDS from BRUKER axs;

Target: Cu;

Filter: none;

Voltage: 40 kV; Current: 40 mA;

Exposure time: 3 min.

[2] Differential Scanning Calorimetry (DSC) <Measurement Conditions>

Instrument: DSC 822e from METTLER TOLEDO;Sample amount: 1 to 2 mg;Sample cell: 40-μL aluminium pan;Nitrogen gas flow: 40 mL/min;Heating rate: 10° C./min (25 to 220° C., 25 to 240° C., 25 to 250° C.)

Example A: Crystal of2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicAcid (Type A Crystal)

In Example 9, the obtained purified product was added with ethyl acetate(7 v/w) and stirred at 0 to 30° C. The solution was filtered once, addedwith toluene (3 v/w), added with a seed crystal and stirred at 25° C.for 3 hours. The mixture was added with toluene (10 v/w), cooled to 0°C. and stirred for 1.5 hours. The resulting crystal was filtered andwashed with toluene (2 v/w) to give the titled crystal. The X-ray powderdiffraction spectrum and the differential scanning calorimetry (DSC)chart of the resulting crystal are shown in FIGS. 1 and 2, respectively.The diffraction angle 20 and relative intensity in the X-ray powderdiffraction spectrum are shown in the following table.

X-Ray Powder Diffraction Spectrum:

TABLE 1 Diffraction angle 2θ (degree) Relative intensity (%) 6.6 100 7.914.8 9.5 91.9 10.1 25.4 13.0 46 13.4 42.9 14.0 24.2 15.3 18.5 16.6 39.517.3 44.6 18.3 49.5 19.0 47.8 19.6 50.1 20.0 31.3 21.1 18 22.8 23.6 23.523 23.8 23.8 24.4 14

The present crystal showed the onset of the endothermic peak at about143° C.

Example B: Crystal of2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoicAcid (Type A Crystal)

The compound prepared in Example 9(20) was added with ethanol (35 v/w)and water (10 v/w). The mixture was heated in an oil bath at 70° C. fordissolution. The solution was allowed to cool from 70° C. to 25° C. andthe resulting crystal was then collected by filtration and dried underreduced pressure to give the titled crystal. The resulting crystal wasanalyzed and the X-ray powder diffraction spectrum and the differentialscanning calorimetry chart thereof are shown in FIGS. 3 and 4,respectively. The diffraction angle 2θ and relative intensity in theX-ray powder diffraction spectrum are shown in the following table.

X-Ray Powder Diffraction Spectrum:

TABLE 2 Diffraction angle 2θ Relative intensity (degree) (%) 5.8 17.47.3 100 8.8 10.5 9.7 9.7 10.5 10.5 11.4 16.6 11.6 17.3 12.4 11.3 13.714.6 14.3 14.1 15.1 32.9 15.7 15 16.7 63.1 17.3 27 18.3 31 19.5 40.520.3 23 21.0 35 21.4 38.6 22.7 23.6 23.5 11.5 24.7 40.1

The present crystal showed the onset of the endothermic peak at about170° C.

Example C: Crystal of1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1-piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxylicAcid (Type A Crystal)

The compound prepared in Example 13 was added with 15 μL of ethanol (15v/w). The mixture was heated in an oil bath at 70° C. for dissolution.The solution was allowed to cool from 70° C. to 25° C. and the resultingcrystal was then collected by filtration and dried under reducedpressure to give the titled crystal. The resulting crystal was analyzedand the X-ray powder diffraction spectrum and the differential scanningcalorimetry (DSC) chart thereof are shown in FIGS. 5 and 6,respectively. The diffraction angle 20 and relative intensity in theX-ray powder diffraction spectrum are shown in the following table.

X-Ray Powder Diffraction Spectrum:

TABLE 3 Diffraction angle 2θ Relative intensity (degree) (%) 7.7 82.511.9 35.2 14.0 22.7 15.6 40.8 16.3 42.2 16.7 100 17.8 94.9 18.3 39.618.9 54.3 19.4 27.9 19.9 36.7 20.2 74.2 21.3 73.3 21.7 41.6 22.4 37.422.9 47.9 23.3 40.3 24.1 26

The present crystal showed the onset of the endothermic peak at about182° C.

EXPERIMENTAL EXAMPLES

The effects of the present compounds were verified based on theexperimental methods shown hereinbelow as the biological experimentalexample and physical experimental example.

Biological Experimental Example 1: Evaluation of S1P₂ AntagonisticActivity by Monitoring the Change in Intracellular Calcium IonConcentration

Chinese hamster ovary (CHO) cells overexpressing the human S1P₂ genewere cultured in a Ham's F12 medium containing 10% fetal bovine serum(FBS), an antibiotic/antifungal agent and G418. CHO cells overexpressingthe rat S1P₂ gene were cultured in a Ham's F12 medium containing 10%FBS, penicillin/streptomycin and blasticidin S. The cultured cells wereincubated in a Fura2-AM solution (5 μM) [a Ham's F12 medium containingFBS (10%), HEPES buffer (20 mM, pH 7.2 to 7.5) and probenecid (2.5 mM)]at 37° C. for 60 minutes. The cells were washed twice with a Hanks'balanced saline containing HEPES buffer (20 mM, pH 7.2 to 7.5) andprobenecid (2.5 mM) and immersed in the same solution. A plate wasmounted on a fluorescence-based drug screening system and theintracellular calcium ion concentration was measured for 30 secondswithout stimulation. A test substance (the final concentration of humanS1P₂: 0.25 nM to 25 μM and the final concentration of rat S1P₂: 0.25 nMto 2.5 μM) or a dimethyl sulphoxide (DMSO) solution was added and after3 minutes SIP (final concentration: 300 nM) was added and the increasein the intracellular calcium ion concentration before and after theaddition of SIP was measured with an interval of 3 seconds (excitationwavelength: 340 nm and 380 nm, fluorescence wavelength: 540 nm).

The S1P₂ antagonistic activity was calculated using the suppressionobtained from the following formula, wherein A is a control value whichwas a peak value after addition of SIP (final concentration: 300 nM) inthe wells added with DMSO without a test substance and B is an increasedamount after addition of SIP in the cells treated with the testsubstance:

Suppression (%)=[(A−B)/A]×100  [E 1]

IC₅₀ value was calculated as the concentration of the present compoundwhich showed the 50% suppression.

Comparative compounds used were the compounds disclosed in Example 1(64)(hereinafter referred to as comparative compound A) and Example 1(85)(hereinafter referred to as comparative compound B) in Patent Document 3(WO 2004/002531). The structural formulae of the comparative compoundsare shown below respectively.

The human and rat S1P₂ antagonistic activities of the present compoundsand comparative compounds are shown in the following Table 4.

TABLE 4 S1P₂ antagonistic activity IC₅₀ (nM) Compound Human RatComparative compound A 1600 72 Comparative compound B 1200 27 Example 15(1) 7.0 9.6 Example 9 (3) 6.2 3.3 Example 15 (6) 5.1 5.0 Example 9 2.32.5 Example 13 3.0 3.0 Example 19 9.4 1.7 Example 38 3.4 1.0

As a result, it was found that the present compounds have significantlyimproved human S1P₂ antagonistic activity compared to the comparativecompounds. In addition, the present compounds also have improveddifference in the S1P₂ antagonistic activity between species, i.e.between human and rat and thus may allow extrapolation of the efficacyobtained in rat pathological models to human.

Physical Experimental Example 2: Solubility Measurement

A solution for obtaining a calibration curve was prepared by diluting atest substance (10 mmol/L, DMSO solution) in acetonitrile and addingacetonitrile containing an internal standard substance (warfarin) toadjust to 0.1, 0.4 and 2 μmol/L. A sample solution was prepared byadding to 495 μL (pH 6.8) of the second solution defined in JapanesePharmacopoeia (a solution used was obtained by adding water to 250 mL ofa 0.2 mol/L potassium dihydrogen phosphate reagent solution and 118 mLof a 0.2 mol/L sodium hydroxide reagent solution to adjust to 1000 mL) 5μL of a test substance (10 mmol/L, DMSO solution), stirring at roomtemperature for 5 hours, transferring the obtained solution to a platewith a filter for vacuum filtration, diluting 20 μL of the filtrate withacetonitrile and adding acetonitrile containing the internal standard.The solution for obtaining a calibration curve and the sample solution(5 μL each) were injected to LC-MS/MS (Discovery Max from ThermoScientific) for quantification (quantification range: 0.1 to 2 μmol/L).The solubility was calculated by multiplying the quantified value by 50.When the calculated value was outside of the quantification range, thesolubility was expressed as <5 μmol/L or 100 μmol/L.

The solubility of the present compounds and the comparative compounds isshown in the following Table 5.

TABLE 5 Compound Solubility (μmol/L) Comparative compound A <5Comparative compound B <5 Example 9 (1) 80.3 Example 9 (3) 90.1 Example9 77.2 Example 19 78.3 Example 38 70.0

As a result, it was found that the present compounds have superiorsolubility than the comparative compounds.

FORMULATION EXAMPLES Formulation Example 1

The following components were mixed and then compressed to make tabletsaccording to the conventional method to obtain 10,000 tabletsrespectively containing 10 mg of the active ingredient.

4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxy-1- 100 gpiperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidine carboxamideCarboxymethylcellulose calcium (disintegrating agent)  20 g Magnesiumstearate (lubricant)  10 g Microcrystalline cellulose 870 g

Formulation Example 2

The following components were mixed according to the conventionalmethod, then filtered through a dust removal filter, divided at 5 ml perampoule, sterilized by heating in an autoclave to obtain 10,000 ampoulesrespectively containing 20 mg of the active ingredient.

1-{4-[3-(4-fluorophenoxy)-5-({[4-hydroxy-4-(3-pentanyl)-1- 200 gpiperidinyl]carbonyl}amino)phenoxy]phenyl} cyclopropanecarboxylic acidMannitol  20 g Distilled water  50 L

INDUSTRIAL APPLICABILITY

The present compound has high human S1P₂ antagonistic activity and thusis useful for therapy of S1P₂-mediated diseases such as diseasesresulting from vascular constriction and fibrosis.

1. A method of preparing a compound of formula (I-A):

wherein R¹ is (1) a C1-8 alkyl group which may be substituted with 1 to5 R²¹ groups, (2) a C2-8 alkenyl group which may be substituted with 1to 5 R²¹ groups, (3) a C2-8 alkynyl group which may be substituted with1 to 5 R²¹ groups, (4) a C3-7 carbocycle which may be substituted with 1to 5 substituents selected from the group consisting of a C1-4 alkylgroup, a C1-4 haloalkyl group, a C1-4 alkoxy group and a halogen atom,or (5) —CONR³¹R³²; R²¹ is (1) a halogen atom, (2) —OR²² (wherein, R²² is(1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkylgroup), (3) —NR²³R²⁴ (wherein, R²³ and R²⁴ each independently are (1) ahydrogen atom or (2) a C1-4 alkyl group) or (4) an oxo group; R³¹ andR³² each independently are (1) a hydrogen atom or (2) a C1-4 alkylgroup; R³ and R⁴ each independently are (1) a halogen atom, (2) a C1-4alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) ahydroxy group, (6) -L-CONR⁶R⁷, (7) -L-SO₂R⁸ or (8) -L-COOR⁹; R⁵ is (1) ahalogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group; L is(1) a bond, (2) a group represented by the formula:

wherein A is (1) a bond or (2) an oxygen atom; R¹² and R¹³ eachindependently are (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) ahydroxy group or (4) NH₂ or (5) R¹² and R¹³ together with the carbonatom to which they are attached may form a C3-7 carbocycle; and thearrow on the right hand side binds to —CONR⁶R⁷, —SO₂R⁸ or —COOR⁹, (3) aC2-4 alkenylene group, (4) a —O—C2-4 alkenylene group, (5) an oxygenatom or (6) a nitrogen atom which may be substituted with a C1-4 alkylgroup; R⁶ and R⁷ each independently are (1) a hydrogen atom, (2) a C1-4alkyl group, (3) a C1-4 haloalkyl group, (4) a hydroxy group, (5)—CONR¹⁵R¹⁶, (6) —SO₂NR¹⁵R¹⁶, (7) —COR¹⁷ or (8) —SO₂R¹⁷, or R⁶ and R⁷together with the nitrogen atom to which they are attached may form a 4-to 7-membered nitrogen-containing saturated heterocycle that may besubstituted with a hydroxy group; R⁸ is (1) a C1-4 alkyl group, (2) aC1-4 haloalkyl group or (3) NR¹⁰R¹¹; R⁹ is (1) a hydrogen atom or (2) aC1-8 alkyl group; R¹⁰ and R¹¹ each independently are (1) a hydrogenatom, (2) a C1-4 alkyl group, (3) —CONR¹⁵R¹⁶, (4) —SO₂NR¹⁵R¹⁶, (5)—COR¹⁷ or (6) —SO₂R¹⁷; the ring 1 and the ring 2 each independently area 5- to 7-membered cyclic group; R¹⁵ and R¹⁶ each independently are (1)a hydrogen atom, (2) a C1-4 alkyl group or (3) a 5- to 7-membered cyclicgroup; R¹⁷ is (1) a C1-4 alkyl group or (2) a 5- to 7-membered cyclicgroup; n is an integer of 1 to 2; m is an integer of 1 to 2; p is aninteger of 0 to 5; q is an integer of 0 to 5; r is an integer of 0 to 4;t is an integer of 1 to 4; when p is 2 or more, a plurality of R³ groupsmay be the same or different; when q is 2 or more, a plurality of R⁴groups may be the same or different; when r is 2 or more, a plurality ofR⁵ groups may be the same or different; and when t is 2 or more, aplurality of R¹² and R¹³ groups may be respectively the same ordifferent, or a salt thereof, wherein the method comprises: reacting acompound of formula (E):

wherein T is a protecting group of the amino group and the other symbolshave the same definitions as above, in the presence of a base with acompound of formula (V)

wherein all symbols have the same definitions as above, in an organicsolvent.
 2. The method according to claim 1, wherein the ring 1 and thering 2 each independently are (1) a benzene, (2) cyclohexane or (3)pyridine ring.
 3. The method according to claim 1, wherein the compoundof formula (I-A) is2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid or a salt thereof.
 4. The method according to claim 1, wherein theprotecting group T comprises a carbonyl group.
 5. The method accordingto claim 4, wherein the protecting group T is a2,2,2-trichloroethoxycarbonyl (Troc) group, a phenoxycarbonyl group, ora p-nitrophenoxycarbonyl group.
 6. The method according to claim 2,wherein the compound of formula (I-A) is2-{4-[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoicacid or a salt thereof.
 7. The method according to claim 1, wherein thering 1 and the ring 2 each independently are a benzene.
 8. The methodaccording to claim 2, wherein the ring 1 and the ring 2 eachindependently are a benzene.
 9. The method according to claim 1, whereinthe base is selected from the group consisting of pyridine,triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine, or a mixture thereof.
 10. The method according toclaim 1, wherein the organic solvent is selected fromN,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and a mixture thereof.
 11. The method according toclaim 2, wherein the base is selected from the group consisting ofpyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine, or a mixture thereof.
 12. The method according toclaim 2, wherein the organic solvent is selected fromN,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and a mixture thereof.
 13. The method according toclaim 3, wherein the base is selected from the group consisting ofpyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine, or a mixture thereof.
 14. The method according toclaim 3, wherein the organic solvent is selected fromN,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and a mixture thereof.
 15. The method according toclaim 7, wherein the base is selected from the group consisting ofpyridine, triethylamine, dimethylaniline, dimethylaminopyridine,diisopropylethylamine, or a mixture thereof.
 16. The method according toclaim 7, wherein the organic solvent is selected fromN,N-dimethylacetamide, chloroform, dichloromethane, diethyl ether,tetrahydrofuran, and a mixture thereof.